Fenofibrate Anti-Cancer Drug

Fenofibrate_prevents _endothelial Cancer_Migration_figure6Fenofibrate, an Old Lipid Drug is also an Anti-Cancer Drug

Fenofibrate is an old lipid lowering drug used since 1975 to treat hyper-triglyceridemia and mixed dyslipidemia by way of activating the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor.(5) Above image courtesy of Tomas Koltai Article.

Fenofibrate Effective in Mantle cell Lymphoma

F3 Fenofibrate Binds to Nuclear receptorIn 2010 Leukemia Dr. Zak published his in-vitro study using fenofibrate in-vitro against mantle cell Lymphoma.(1)  Dr Zak reports fenofibrate is an agonist for peroxisome proliferator-activated receptor-alpha (PPAR-alpha), and induces apoptosis in Mantle Cell Lymphoma cells (in-vitro),(1)   In addition, fenofibrate significantly downregulated tumor necrosis factor-alpha (TNF-alpha) and also decreased the nuclear translocation of nuclear factor (NF-KB)–p65, and inhibited the DNA binding of NF-kappaB . (1)  Dr Zak states that effective serum levels of fenofibrate can be achieved at clinically relevant doses up to 400 mg per day, taken with the evening meal, which is well tolerated without significant adverse effects. (36-37)

Left image : Classical fenofibrate signaling pathway. Fenofibrate is rapidly converted to fenofibric acid (FA) in vivo by tissue and plasma esterases before entering the cell. Fenofibric acid (FA) binds to PPARα and forms a heterodimer complex with retinoid X receptor (RXR). This complex then binds to specific peroxisome proliferator response elements (PPREs) to activate target gene transcription. RA, 9-cis retinoic acid.

Regulating Lipid metabolism

In 2013 Dr. Huang further elucidated the effect of fenofibrate on B cell lymphoma in a xenograft mouse model.(2) Dr Huang found that B Cell lymphomas hi-jack host lipid metabolism to recruit fatty acids to fuel rapid growth. He says:

“B-cell tumors trigger systemic lipid mobilization from WAT (White Adipose tissue) to the liver and increase VLDL/LDL release from the liver to promote tumor growth.”

Dr Huang found that fenofibrate significantly suppressed tumor growth independent of angiogenesis and inflammation.(2) The mechanism was related to (white adipose tissue) WAT depletion, stimulation of (free fatty acid) FFA uptake by the liver and restoration of hepatic (fatty acid) FA oxidation.  Fenofibrate accelerated clearance of serum lipids, and blocked hepatic lipid release induced by the tumors. Dr Huang concluded that fenofibrate associated effects on hepatic lipid metabolism with deprivation of serum lipids suppresses B-cell lymphoma growth, serving as a novel treatment strategy.(2)

Fenofibrate Accumulates in Mitochondrial Fraction- Inhibits Complex 1 E.T.C.-Inhibits mTOR – Glioblastoma Model In Vitro

Dr Anna Wilk studied the effect of fenofibrate on glioblastoma cells in vitro in her 2015 paper.(3)  Dr Wilk found that fenofibate accumulates in the mitochondrial fraction, with inhibition of complex I of the electron transport chain (ETC), similar to Metformin.  Thus the cancer cell metabolism is switched from Fatty Acid Oxidation (OxPhos) phenotype to glycolytic phenotype which “depletes intracellular ATP, activates the AMP-activated protein kinase–(mTOR) mammalian target of rapamycin–autophagy pathway, and results in extensive tumor cell death….autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity.”(3) Dr Anna Wilk says:

Fenofibrate accumulates in the mitochondrial fraction of human glioblastoma cells. As a consequence, these neoplastic cells respond with a sudden and severe inhibition of mitochondrial respiration and an immediate but transient increase in glycolysis. We further demonstrate that complex I of the electron transport chain (ETC) is the preferred target of mitochondrial FF. The subsequent decline in intracellular ATP preceded the activation of AMP-activated protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) activity….

Here we report a novel PPARα-independent mechanism explaining (fenofibrate) FF’s cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF (fenofibrate) in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPARα-dependent metabolic switch from glycolysis to fatty acid β-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase–mammalian target of rapamycin–autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity.”(3)

Another Lymphoma/Myeloma in vitro study by Dr Schmeel in 2017 AntiCancer Research showed:

Fenofibrate significantly reduced viability due to apoptosis induction in all investigated myeloma and lymphoma cell lines in a dose-dependent manner“.(4)

Dr Tomas Koltai studied the anticancer activity of fenofibrate in 2015.(5) He reports:

The main mechanisms of anti-cancer activity:

1) anti-angiogenesis through down-regulation of Vascular Endothelial Growth Factor (VEGF), Vascular Endothelial Growth Factor Receptor (VEGFR) and Hypoxia Inducible factor-1 a (HIF-1a),
2) inhibition of endothelial cell migration

Apoptosis and cell cycle arrest mechanism include:

1) down-regulation of Nuclear Factor Kappa B (NF-kB) and Protein kinase B (Akt)
2) decrease of cellular energy by impairing mitochondrial function
3) Growth impairment from down-regulation of Phospho-Inositol 3 Kinase (PI3K)/Akt axis and down-regulation of the p38 map kinase (MAPK) cascade.

Anti-metastatic activities of Fenofibrate:

1) Down-regulation of MCP-1 (monocyte chemotactic protein-1),
2) decreased Metalloprotease-9 (MMP-9) production,
3) weak down-regulation of adhesion molecules like E selectin, intercellular adhesion molecules (ICAM) and Vascular Endothelial Adhesion Molecules (VCAM)
4) decreased secretion of chemokines like Interleukin-6 (IL-6), and down-regulation of cyclin D-1.

Angiogenesis Inhibition Potentiated by ATRA (All-Trans-Retinoic Acid)

Angiogenesis inhibition is one of the main anti-tumor activities of FF.  “Nickkho-Amiry et al.28 showed that treatment of human endometrial cells with a PPARα agonist leads to reduced secretion of VEGF in addition to reduced proliferation. This was potentiated by RxR (Retinoid X receptor) agonist like ATRA.”(5)

Dr Samir found anti-cancer effects of fenofibrate were potentiated by retinoic acid (ATRA) in endometrial cancer cells. (35)  They found the combination downregulated Cyclin D1 (CCND1)  and cell cycle progression.

Fenofibrate, an agonist of PPAR-alpha, in doses above 25 μM, inhibits proliferation

Combination of 2-DG and Fenofibrate found effective for Variety of Cancers

Combination of 2-DG given I.V. along with daily Fenofibrate was found effective for a variety of cancers. Fenofibrate is typically administered orally in a dosage of 40 mg to 120 mg per day, achieving plasma concentration of about 10 μΜ to about 50 μΜ. (8-10)  2-De-Oxy-Glucose (2 DG) is a glycolysis inhibitor.(8-10)  Alternatively, High dose IV Vitamin C may be used as a glyolysis inhibitor.   See IV vitamin C as Cancer chemotherapy.

PPAR Alpha Degrades BCL2 Protein

Dr Gao in 2015 Oncotarget found that PPARalpha binds to BCL2 and promotes its degradation through ubiquitination and degradation by the proteosome.(15)   Thus reducing cancer cell chemoresistance to apoptosis.(14)  Dr Eucker in 2014 reported Mantle Cell lymphoma has high expression of Peroxisome proliferator-activated receptor-gamma protein, and PPAR ligands (such as fenfibrate) induce apoptosis  at 50 micromol/l  .(15)

Reduction in Cyclin D1 expression in Mantle cell Lymphoma

Dr Zak reported in Leukemia 2010 that fenfibrate induces effective apoptosis in Mantle cell lymphoma by inhibiting TNF-alpha and NF-KB signaling.(1)  They also reported fenofibrate downregulates expression of Cyclin D1 (see Fig.4).(1)

Adverse Effects of Fenofibrate – Mitochondrial Toxicity

Fenofibrate impairs Complex I of the Electron Transport Chain in the Mitochondria, and are therefore considered mitochondrial toxins.(28-31)  This effect may be magnified by accumulation of the drug in the mitochondria, where it is considered useful as an anticancer drug in a Glioblastoma model.(30)

Conclusion: Fenfibrate, the old lipid drug,  has considerable anti-cancer activity and should be available on the oncology wards as a re-purposed anti-cancer drug.

Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Fl 33314
954-792-4663
www.jeffreydachmd.com

Articles with related Interest:

Clarithromycin Anti-Cancer Drug

Itraconazole Anticancer Antifungal Drug

COX2 Inhibitor Celecoxib as AntiCancer Drug

Doxycycline Vitamin C AntiCancer Synergy

Metformin Repurposed Anticancer Drug

Links and References:

Above images courtesy of: An Update on the Molecular Actions of Fenofibrate and Its Clinical Effects on Diabetic Retinopathy and Other Microvascular End Points in Patients With Diabetes Jonathan E. Noonan1, Alicia J. Jenkins2,3,4, Jian-Xing Ma4, Anthony C. Keech3, Jie Jin Wang5 and Ecosse L. Lamoureux1,6,7,8⇑ Diabetes 2013 Dec; 62(12): 3968-3975.

1) Leukemia. 2010 Aug;24(8):1476-86. Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFalpha/NF-kappaB signaling axis.  Fenofibrate induces effective apoptosis in mantle cell lymphoma  Zak Z1, Gelebart P, Lai R.

Mantle cell lymphoma (MCL) is a type of aggressive B-cell non-Hodgkin’s lymphoma characterized by frequent resistance to conventional chemotherapy. In this study we provided evidence that fenofibrate, which is widely known as an agonist for peroxisome proliferator-activated receptor-alpha (PPARalpha), can induce effective apoptosis in treating MCL cells.

Addition of fenofibrate to MCL cell lines significantly decreased the number of viable cells by 50% at approximately 20 microM at 72 h. This decrease in cell growth was due to apoptosis, as evidenced by the cleavage of caspase 3 and poly(ADP-ribose) polymerase. The fenofibrate-mediated effects were not significantly affected by GW6471, a specific PPARalpha antagonist.

Using an apoptosis pathway-specific oligonucleotide array, we found that fenofibrate significantly downregulated several pro-survival genes, including tumor necrosis factor-alpha (TNFalpha). Importantly, addition of recombinant TNF-alpha conferred partial protection against fenofibrate-induced apoptosis. Fenofibrate also decreased the nuclear translocation of nuclear factor (NF)-kappaB-p65 and significantly inhibited the DNA binding of NF-kappaB in a dose-dependent manner. To conclude, fenofibrate shows efficacy against MCL, and the mechanism can be attributed to its inhibitory effects on the TNF-alpha/NF-kappaB signaling axis. In view of the documented safety of fenofibrate in humans, it may provide a valuable therapeutic option for MCL patients.


2) Huang, Jianfeng, et al. “The PPARa agonist fenofibrate suppresses B-cell lymphoma in mice by modulating lipid metabolism.” Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1831.10 (2013): 1555-1565.

In wild-type mice, tumor size significantly correlated with depletion of white adipose tissues (WAT), resulting in increased serum free fatty acid (FFA) concentrations which promote B-cell proliferation in vitro.

Moreover, B-cell tumor development induced hepatic lipid accumulation due to enhanced hepatic fatty acid (FA) uptake and impaired FA oxidation. Serum triglyceride, FFA, phospholipid and cholesterol levels were significantly elevated. Consistently, serum VLDL/LDL-cholesterol and apolipoprotein B levels were drastically increased.

These findings suggest that B-cell tumors trigger systemic lipid mobilization from WAT to the liver and increase VLDL/LDL release from the liver to promote tumor growth. Further support for this concept stems from experiments where we used the peroxisome proliferator-activated receptor α (PPARα) agonist and lipid-lowering drug fenofibrate that significantly suppressed tumor growth independent of angiogenesis and inflammation. In addition to WAT depletion, fenofibrate further stimulated FFA uptake by the liver and restored hepatic FA oxidation capacity, thereby accelerating the clearance of lipids released from WAT. Furthermore, fenofibrate blocked hepatic lipid release induced by the tumors. In contrast, lipid utilization in the tumor tissue itself was not increased by fenofibrate which correlates with extremely low expression levels of PPARα in B-cells. Our data show that fenofibrate associated effects on hepatic lipid metabolism and deprivation of serum lipids are capable to suppress B-cell lymphoma growth which may direct novel treatment strategies.

3) Wilk, Anna, et al. “Molecular mechanisms of fenofibrate-induced metabolic catastrophe and glioblastoma cell death.” Molecular and cellular biology 35.1 (2015): 182-198.

The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPARa-dependent metabolic switch from glycolysis to fatty acid ß-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase–mammalian target of rapamycin–autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity.

The primary and conventional function of FF is the activation of PPARa transcriptional activity.

 Lymphoma/Myeloma

4) Anticancer Res. 2017 Jul;37(7):3513-3520.
In Vitro Apoptosis Induction by Fenofibrate in Lymphoma and Multiple Myeloma.  Schmeel LC1,2, Schmeel FC1,2, Schmidt-Wolf IGH3.
Recent innovations in the treatment of multiple myeloma have enriched our therapeutic repertoire regarding the treatment of multiple myeloma during the last decades. However, despite today’s therapies many multiple myeloma (MM) patients experience relapse of disease and eventually remain incurable. Wnt/β-catenin signaling has been demonstrated in lymphoma and MM, rendering related signaling molecules promising therapeutic targets. Fenofibrate, an extensively scrutinized and widely used drug for primary hypercholesterolemia or mixed dyslipidemia, has proven anticarcinogenic properties mediated by peroxisome proliferator-activated receptor-alpha (PPARα) agonism, thereby also influencing WNT-associated signaling molecules.
MATERIALS AND METHODS:  The antitumor apoptotic effect of fenofibrate at doses ranging from 0.1-200 μM was investigated on a total of seven human, two murine myeloma/lymphoma cell lines and two healthy control cell lines, as determined by 3’3-Dihexyloxacarbocyanine iodide (DiOC6) and propidium iodide (PI) staining in flow cytometry.
RESULTS:  Fenofibrate significantly reduced viability due to apoptosis induction in all investigated myeloma and lymphoma cell lines in a dose-dependent manner, whereas healthy control cells were less sensitive.
CONCLUSION:  Our results provide a rationale for future in vitro and in vivo studies with fenofibrate as a safe and well-tolerated agent in MM and lymphoma treatment.

 

5) Koltai, Tomas. “Fenofibrate in cancer: mechanisms involved in anticancer activity.” F1000Research 4 (2015).

Fenofibrate (FF) is a drug of the fibrate class (a fibric acid derivative)
(for chemical structure, see Figure 1) that has been used since 1975 to reduce cholesterol (LDL and VLDL) and triglyceride levels and increase HDL in patients at risk of cardiovascular disease and for treatment of atherosclerosis (1 and 47). FF is one of the most commonly prescribed fibrates, and has a well known efficacy and tolerability profile1.

FF seems to lower lipid levels by activating peroxisome proliferator-
activated receptor alpha (PPARa), a nuclear receptor

Results: The main mechanism involved in anti-cancer activity is anti-angiogenesis through down-regulation of Vascular Endothelial Growth Factor (VEGF), Vascular Endothelial Growth Factor Receptor (VEGFR) and Hypoxia Inducible factor-1 a (HIF-1a), inhibition of endothelial cell migration, up-regulation of endostatin and thrombospondin-1, but there are many other contributing mechanisms like apoptosis and cell cycle arrest, down-regulation of Nuclear Factor Kappa B (NF-kB) and Protein kinase B (Akt) and decrease of cellular energy by impairing mitochondrial function. Growth impairment is related to down-regulation of Phospho-Inositol 3 Kinase (PI3K)/Akt axis and down-regulation of the p38 map kinase (MAPK) cascade. A possible role should be assigned to FF stimulated over-expression of Tribbles Homolog-3 (TRIB3) which inhibits Akt phosphorylation. Important anti-cancer and anti-metastatic activities are due to down-regulation of MCP-1 (monocyte chemotactic protein-1), decreased Metalloprotease-9 (MMP-9) production, weak down-regulation of adhesion molecules like E selectin, intercellular adhesion molecules (ICAM) and Vascular Endothelial Adhesion Molecules (VCAM), and decreased secretion of chemokines like Interleukin-6 (IL-6), and down-regulation of cyclin D-1. There is no direct link between FF activity in lipid metabolism and anticancer activity, except for the fact that many anticancer actions are dependent from PPARa agonism. FF exhibits also PPARa independent anti-cancer activities.
Conclusions: There are strong evidences indicating that FF can disrupt growth-related activities in many different cancers, due to anti-angiogenesis and anti-inflammatory effects. Therefore FF may be useful as a complementary adjunct treatment of cancer, particularly included in anti-angiogenic protocols like those currently increasingly used in glioblastoma. There are sound reasons to initiate well planned phase II clinical trials for FF as a complementary adjunct treatment of cancer.

Youssef and Badr in 1998168 and Zungu et al.169 described the derangement of mitochondrial function due to peroxisome proliferator drugs. FF acts as an inducer of mitochondrial citrate synthase and NADH oxidase activity170 and Scatena et al.171 identified these mitochondrial changes in the respiratory chain consisting in inhibition of NADH cytochrome c reductase activity in a dose dependent manner. They also described that mitochondrial activities of FF were PPARa independent172,173.

6) Gou, Qian, et al. “Peroxisome proliferator-activated receptors (PPARs) are potential drug targets for cancer therapy.” Oncotarget 8.36 (2017): 60704.

Triple Neg Breast cancer

7) Li, Ting, et al. “Fenofibrate induces apoptosis of triple-negative breast cancer cells via activation of NF-KappaB pathway.” BMC cancer 14.1 (2014): 96.
It is concluded that fenofibrate induces apoptosis of TNBC via activation of NF-KB pathway in a PPAR-a independent way, and may serve as a novel therapeutic drug for TNBC therapy.

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8) Liu, Huaping, et al. “Combining 2-deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress.” Oncotarget 7.24 (2016): 36461.

Unregulated growth and replication as well as an abnormal microenvironment, leads to elevated levels of stress which is a common trait of cancer. By inducing both energy and endoplasmic reticulum (ER) stress, 2-Deoxy-glucose (2-DG) is particularly well-suited to take advantage of the therapeutic window that heightened stress in tumors provides. Under hypoxia, blocking glycolysis with 2-DG leads to significant lowering of ATP resulting in energy stress and cell death in numerous carcinoma cell types. In contrast, under normoxia, 2-DG at a low-concentration is not toxic in most carcinomas tested, but induces growth inhibition, which is primarily due to ER stress. Here we find a synergistic toxic effect in several tumor cell lines in vitro combining 2-DG with fenofibrate (FF), a drug that has been safely used for over 40 years to lower cholesterol in patients. This combination induces much greater energy stress than either agent alone, as measured by ATP reduction, increased p-AMPK and downregulation of mTOR. Inhibition of mTOR results in blockage of GRP78 a critical component of the unfolded protein response which we speculate leads to greater ER stress as observed by increased p-eIF2α. Moreover, to avoid an insulin response and adsorption by the liver, 2-DG is delivered by slow-release pump yielding significant anti-tumor control when combined with FF. Our results provide promise for developing this combination clinically and others that combine 2-DG with agents that act synergistically to selectively increase energy and ER stress to a level that is toxic to numerous tumor cell types.

patent  Theodore J. Lampidis

9) Combination therapy with fenofibrate and 2-deoxyglucose or 2-deoxymannose
WO 2016065353 A1

Fenofibrate (propan-2-yl 2-{4-[(4-chlorophenyl)carbonyl]phenoxy}-2- methylpropanoate; abbreviated FF) is a drug that has been prescribed for decades to treat high cholesterol. The majority of the FF administered is metabolized in vivo to fenofibric acid via hydrolysis of the carboxyl ester moiety. FF is thought to lower cholesterol and triglycerides by activating peroxisome proliferator- activated receptor alpha (PPARa), which in turn activates lipoprotein lipase, thereby increasing lipolysis and eliminating triglyceride-rich particles from the blood. FF is typically administered orally in a dosage of 40 mg to 120 mg per day for this indication.

the FF is administered in an amount effective to achieve a plasma FF concentration of about 10 μΜ to about 50 μΜ. Optionally, the FF is administered in an amount effective to achieve a plasma fenofibric acid concentration of less than about 10 μΜ.

Publication number WO2016065353 A1
Publication type Application
Application number PCT/US2015/057333
Publication date Apr 28, 2016
Filing date Oct 26, 2015
Priority date Oct 24, 2014
Inventors Theodore J. Lampidis, Metin Kurtoglu, Huaping Liu
Applicant University Of Miami

10) Tumor Evolution & Progression Ted Lampidis
Combining 2-DG and Fenofibrate Kills a Wide Variety of Cancers

Using a combination of 2-DG (2-Deoxy-D-glucose) and fenofibrate effectively exploits 2 universal cancer traits – increased glucose uptake and increased stress – to effectively target the entire tumor, paving the way for a universal cancer treatment.

What is the research problem :  Chemotherapy attacks only the fast growing outer cells of a tumor, not the slow growing inner cells (which are the most metastatic), as well as killing healthy cells. Further, targeted therapies are unable to simultaneously attack the entire tumor.

How will your solution make a difference :  This unique combination of 2-DG and fenofibrate delivers a non-toxic treatment that has so far been shown to be effective in a wide variety of human cancers. Our hope is to bring this non-toxic treatment to millions of cancer patients worldwide.

What is your proposed solution : 2-DG (2-Deoxy-D-glucose), a simple sugar, has been shown to inhibit glycolysis, which the most malignant cancer cells found in the inner core of all solid cancers rely on to survive. Using a combination of 2-DG and fenofibrate (a compound that has been safely used in humans for over 40 years to lower cholesterol and triglycerides), we have proven that the entire tumor can effectively be targeted without the use of toxic chemotherapy.

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Fenofibrate Reverses Endometriosis – Rat Model
Anti-Angiogenesis

11) Fertil Steril. 2009 Dec;92(6):2100-2.  Epub 2009 Jul 5.  Fenofibrate causes regression of endometriotic implants: a rat model.Onalan G1, Zeyneloglu HB, Bayraktar N.
Fenofibrate -a peroxisome proliferator-activated receptor-a agonist- is an angiostatic agent that is commonly used in human liver diseases, therefore it may interfere with the angiogenetic process required for endometriosis. In a rat endometriosis model, we demonstrated that peritoneal implant areas and vascular endothelial growth factor levels in the peritoneal fluid were significantly decreased in high dose or low dose finofibrate and luprolide acetate treated groups compared to control.

Mantle Cell-NFKB and MTOR Targeting

12) Chaturvedi, Nagendra K., et al. “Novel treatment for mantle cell lymphoma including therapy-resistant tumor by NF-KB and mTOR dual-targeting approach.” Molecular cancer therapeutics 12.10 (2013): 2006-2017.
Mantle cell lymphoma (MCL) is one of the most aggressive B cell non-Hodgkin lymphomas with a median survival of about five years. Currently, there is no curative therapy available for refractory MCL because of relapse from therapy-resistant tumor cells. The NF-KB and mTOR pathways are constitutively active in refractory MCL leading to increased proliferation and survival. Targeting these pathways is an ideal strategy to improve therapy for refractory MCL. Therefore, we investigated the in vitro and in vivo antilymphoma activity and associated molecular mechanism of action of a novel compound 13-197, a quinoxaline analog that specifically perturbs I?B kinase (IKK) ß, a key regulator of the NF-KB pathway. 13-197 decreased the proliferation and induced apoptosis in MCL cells including therapy-resistant cells compared to control cells. Furthermore, we observed down-regulation of I?Ba phosphorylation and inhibition of NF-KB nuclear translocation by 13-197 in MCL cells. In addition, NF-KB regulated genes such as cyclin D1, Bcl-XL and Mcl-1 were down-regulated in 13-197-treated cells. 13-197 also inhibited the phosphorylation of S6K and 4E-BP1, the downstream molecules of mTOR pathway that are also activated in refractory MCL. Further, 13-197 reduced the tumor burden in vivo in the kidney, liver, and lungs of therapy-resistant MCL bearing NOD-SCID mice compared to vehicle treated mice; indeed, 13-197 significantly increased the survival of MCL transplanted mice. Together, results suggest that 13-197 as a single agent disrupts the NF-KB and mTOR pathways leading suppression of proliferation and increased apoptosis in malignant MCL cells including reduction in tumor burden in mice.

Mantle Cell – B Cell Receptor and NF-KB Pathways

13) Saba, Nakhle S., et al. “Pathogenic role of B-cell receptor signaling and canonical NF-KB activation in mantle cell lymphoma.” Blood 128.1 (2016): 82-92. To interrogate signaling pathways activated in mantle cell lymphoma (MCL) in vivo, we contrasted gene expression profiles of 55 tumor samples isolated from blood and lymph nodes from 43 previously untreated patients with active disease. In addition to lymph nodes, MCL often involves blood, bone marrow, and spleen and is incurable for most patients. Recently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib demonstrated important clinical activity in MCL. However, the role of specific signaling pathways in the lymphomagenesis of MCL and the biologic basis for ibrutinib sensitivity of these tumors are unknown. Here, we demonstrate activation of B-cell receptor (BCR) and canonical NF-KB signaling specifically in MCL cells in the lymph node. Quantification of BCR signaling strength, reflected in the expression of BCR regulated genes, identified a subset of patients with inferior survival after cytotoxic therapy. Tumor proliferation was highest in the lymph node and correlated with the degree of BCR activation. A subset of leukemic tumors showed active BCR and NF-KB signaling apparently independent of microenvironmental support. In one of these samples, we identified a novel somatic mutation in RELA (E39Q). This sample was resistant to ibrutinib-mediated inhibition of NF-KB and apoptosis. In addition, we identified germ line variants in genes encoding regulators of the BCR and NF-KB pathway previously implicated in lymphomagenesis. In conclusion, BCR signaling, activated in the lymph node microenvironment in vivo, appears to promote tumor proliferation and survival and may explain the sensitivity of this lymphoma to BTK inhibitors.

PPAR-alpha Degrades BCL2

14) Gao, Jiaming, et al. “PPARa induces cell apoptosis by destructing Bcl2.” Oncotarget 6.42 (2015): 44635.

PPARa belongs to the peroxisome-proliferator-activated receptors (PPARs) family, which plays a critical role in inhibiting cell proliferation and tumorigenesis, while the molecular mechanism is still unclear. Here we report that PPARa serves as an E3 ubiquitin ligase to govern Bcl2 protein stability. PPARa physically bound to Bcl2 protein. In this process, PPARa/C102 was critical for PPARa binding to BH3 domain of Bcl2, subsequently, PPARa transferred K48-linked polyubiquitin to lysine-22 site of Bcl2 resulting in its ubiquitination and proteasome-dependent degradation. Importantly, overexpression of PPARa enhanced cancer cell chemotherapy sensitivity. In contrast, silenced PPARa decreased this event. These findings revealed a novel mechanism of PPARa governed endogenous Bcl2 protein stability leading to reduced cancer cell chemoresistance, which provides a potential drug target for cancer treatment.

Here we found that PPARa serves an E3 ubiquitin ligase to induce Bcl2 ubiquitination and degradation leading to cell apoptosis in response to chemotherapy drugs.
PPARa induces Bcl2 degradation
PPARa/Bcl2 signaling increases cancer cell sensitivity in response to chemotherapy drugs

PPAR ligands induce apoptosis in Mantle cell which has

high expression of Peroxisome proliferator-activated receptor-gamma protein

15) Eucker, Jan, et al. “Peroxisome proliferator-activated receptor-gamma ligands inhibit proliferation and induce apoptosis in mantle cell lymphoma.” Anti-cancer drugs 17.7 (2006): 763-769.
Peroxisome proliferator-activated receptor-gamma, a nuclear receptor and transcription factor, and its natural and synthetic ligands have become a focus of novel approaches to induction of apoptosis in solid tumors and hematologic malignancies, including malignant B-lineage cells. The effect on mantle cell lymphoma, a subtype with dismal prognosis, has not yet been analyzed. We investigated the effect of 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), pioglitazone (PGZ) or rosiglitazone (RGZ) on human mantle cell lymphoma cell lines (GRANTA-519, Hbl-2 and JeKo-1). Mantle cell lymphoma cell lines exhibited a high expression of Peroxisome proliferator-activated receptor-gamma protein in Western blot analysis. MTT assays revealed anti-proliferative effects induced by both 15d-PGJ2, the natural activator of Peroxisome proliferator-activated receptor-gamma, and PGZ and RGZ, synthetic Peroxisome proliferator-activated receptor-gamma ligands, in a dose-dependent manner. At a dose of 50 micromol/l, 15d-PGJ2 induced growth inhibition in all cell lines. The anti-proliferative effect of PGZ and RGZ was slightly lower. Induction of apoptosis was indicated by annexin V staining. At a dose of 50 micromol/l, 15d-PGJ2 led to apoptosis in all cell lines (87-99%) after 48 h of incubation. Again, the apoptotic effect with thiazolidinediones was slightly lower at the same dose level. This is the first study evaluating Peroxisome proliferator-activated receptor-gamma expression and its therapeutic implications in human mantle cell lymphoma cells. Thiazolidinediones comprise anti-lymphoma activity in vitro and should be further explored for the treatment of mantle cell lymphoma.

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Orlistat, a FASN (Fatty Acid Synthetase) inhibitor
Effective in Mantle Cell Lymphoma

dramatic decrease in the cyclin D1 level
down-regulated β-catenin

16) Gelebart, Pascal, et al. “Blockade of Fatty Acid Synthase Triggers Significant Apoptosis in Mantle Cell Lymphoma.” PLoS ONE 7.4 (2012).
Fatty acid synthase (FASN), a key player in the de novo synthetic pathway of long-chain fatty acids, has been shown to contribute to the tumorigenesis in various types of solid tumors. We here report that FASN is highly and consistently expressed in mantle cell lymphoma (MCL), an aggressive form of B-cell lymphoid malignancy. Specifically, the expression of FASN was detectable in all four MCL cell lines and 15 tumors examined. In contrast, benign lymphoid tissues and peripheral blood mononuclear cells from normal donors were negative. Treatment of MCL cell lines with orlistat, a FASN inhibitor, resulted in significant apoptosis. Knockdown of FASN expression using siRNA, which also significantly decreased the growth of MCL cells, led to a dramatic decrease in the cyclin D1 level. β-catenin, which has been previously reported to be upregulated in a subset of MCL tumors, contributed to the high level of FASN in MCL cells, Interesting, siRNA knock-down of FASN in turn down-regulated β-catenin. In conclusion, our data supports the concept that FASN contributes to the pathogenesis of MCL, by collaborating with β-catenin. In view of its high and consistent expression in MCL, FASN inhibitors may hold promises for treating MCL.

In this study, we found that FASN is highly and consistently expressed in MCL cell lines and tumors. Importantly, blockade of FASN can induce significant apoptosis in MCL. Our findings suggest that FASN may represent a useful therapeutic target for MCL.

To conclude, the present study describes the high level of FASN expression is a consistent finding in MCL cell lines and tumors. Our data has supported the concept that FASN confers anti-apoptotic effects in MCL cells. Our results also uncovered a positive feedback loop involving FASN and β-catenin, a signaling protein previously reported to be important in the pathobiology of MCL. Thus, inhibition of FASN, possibly in combination with the blockade of β-catenin, may be a useful approach to treat MCL.

17) Bhatt, Aadra P., et al. “Dysregulation of fatty acid synthesis and glycolysis in non-Hodgkin Iymphoma.” Proceedings of the National Academy of Sciences of the United States of America (2012): 11818-11823.
Compared with primary B cells, both aerobic glycolysis and fatty acid synthesis (FAS) are up-regulated in PEL and other types of nonviral B-NHL. We found that aerobic glycolysis and FAS occur in a PI3K-dependent manner and appear to be interdependent. PEL overexpress the fatty acid synthesizing enzyme, FASN, and both PEL and other B-NHL were much more sensitive to the FAS inhibitor, C75, than primary B cells. Our findings suggest that FASN may be a unique candidate for molecular targeted therapy against PEL and other B-NHL.

Cancer Associated Fibroblasts (CAF)

18) Semin Cancer Biol. 2014 Apr;25:47-60.  Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Martinez-Outschoorn UE1, Lisanti MP2, Sotgia F3.

Fibroblasts are the most abundant “non-cancerous” cells in tumors. However, it remains largely unknown how these cancer-associated fibroblasts (CAFs) promote tumor growth and metastasis, driving chemotherapy resistance and poor clinical outcome. This review summarizes new findings on CAF signaling pathways and their emerging metabolic phenotypes that promote tumor growth. Although it is well established that altered cancer metabolism enhances tumor growth, little is known about the role of fibroblast metabolism in tumor growth. New studies reveal that metabolic coupling occurs between catabolic fibroblasts and anabolic cancer cells, in many types of human tumors, including breast, prostate, and head & neck cancers, as well as lymphomas. These catabolic phenotypes observed in CAFs are secondary to a ROS-induced metabolic stress response. Mechanistically, this occurs via HIF1-alpha and NFκB signaling, driving oxidative stress, autophagy, glycolysis and senescence in stromal fibroblasts. These catabolic CAFs then create a nutrient-rich microenvironment, to metabolically support tumor growth, via the local stromal generation of mitochondrial fuels (lactate, ketone bodies, fatty acids, glutamine, and other amino acids). New biomarkers of this catabolic CAF phenotype (such as caveolin-1 (Cav-1) and MCT4), which are reversible upon treatment with anti-oxidants, are strong predictors of poor clinical outcome in various types of human cancers. How cancer cells metabolically reprogram fibroblasts can also help us to understand the effects of cancer cells at an organismal level, explaining para-neoplastic phenomena, such as cancer cachexia. In conclusion, cancer should be viewed more as a systemic disease, that engages the host-organism in various forms of energy-transfer and metabolic co-operation, across a whole-body “ecosystem”.

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Activation of the PI3K/Akt pathway contributes to pathogenesis of MCL  blastoid variants- AKT Inhibitor Useful

Dramatic loss of cyclin D1 following Akt inhibition

19) Blood. 2006 Sep 1;108(5):1668-76. Epub 2006 Apr 27.
Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma.  Rudelius M1, Pittaluga S, Nishizuka S, Pham TH, Fend F, Jaffe ES, Quintanilla-Martinez L, Raffeld M.

To determine whether the PI3K/Akt signaling pathway is involved in the pathogenesis of mantle cell lymphoma (MCL), we investigated the phosphorylation status of Akt and multiple downstream targets in primary MCL cases and cell lines. Akt was phosphorylated in 12 of 12 aggressive blastoid MCL variants and in 4 of 4 MCL cell lines. In contrast, phosphorylated Akt was present in only 5 of 16 typical MCL, 3 at comparable levels to the blastoid cases, and 2 at low levels. The presence of p-Akt was accompanied by the phosphorylation of p27(kip1), FRKHL-1, MDM2, Bad, mTOR, and p70S6K. Inhibition of the PI3K/Akt pathway in the MCL cell lines abrogated or reduced the phosphorylation of Akt, p27(kip1), FRKHL-1, MDM2, Bad, mTOR, GSK-3beta, IkappaB, and led to cell-cycle arrest and apoptosis. Six MCL cases (5 with activated Akt and 1 with inactive Akt) and 3 of 4 cell lines showed loss of PTEN expression. PIK3CA mutations were not detected. We conclude that constitutive activation of the PI3K/Akt pathway contributes to the pathogenesis of MCL and preferentially occurs in blastoid variants. One possible mechanism of activation is loss of PTEN expression. These data suggest that PI3K/Akt inhibitors may be effective in the treatment of Akt-activated MCL.

The PI3K/Akt pathway is preferentially activated in the blastoid variant of MCL and in MCL cell lines

modulation of cyclin D1 levels as a result of pharmacologic manipulation of the PI3K/Akt pathway has not been reported previously in MCL and suggests a potential point of intervention in this disease.
The dramatic loss of cyclin D1 following Akt inhibition potentially could occur through the reactivation of the GSK-3β kinase, which targets cyclin D1 for degradation,

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Artesunate Inhibits TNF alpha production of cytokines by inhibition of NFKB and PI3/Akt/

20) Xu, H., et al. “Anti-malarial agent artesunate inhibits TNF-α-induced production of proinflammatory cytokines via inhibition of NF-κB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes.” (2007): 920-926.

21) Thanaketpaisarn, Oranuch, et al. “Artesunate enhances TRAIL-induced apoptosis in human cervical carcinoma cells through inhibition of the NF-κB and PI3K/Akt signaling pathways.” International journal of oncology 39.1 (2011): 279-285.

Fenfibrate and WNT PAthway

22) Oncogene. 2017 Oct 23. Activation of PPARα by clofibrate sensitizes pancreatic cancer cells to radiation through the Wnt/β-catenin pathway.
Xue J1,2, Zhu W1,2, Song J1,2, Jiao Y1,2, Luo J3, Yu C1,2, Zhou J4, Wu J4, Chen M5, Ding WQ6, Cao J1,2, Zhang S1,2,5.
Radiotherapy is emerging as an important modality for the local control of pancreatic cancer, but pancreatic cancer cell radioresistance remains a serious concern. Peroxisome proliferator-activated receptor α (PPARα) is a member of the PPAR nuclear hormone receptor superfamily, which can be activated by fibrate ligands. The clinical relevance of PPARα and its biological function in pancreatic cancer radiosensitivity have not been previously described. In this study, we examined PPARα expression in tissue samples of pancreatic cancer patients. We found significantly higher expression of PPARα in pancreatic cancer tissues than in tumor-adjacent tissues and that the PPARα expression level is inversely associated with higher overall patient survival rate. We further observed that PPARα activation by its agonist clofibrate sensitizes pancreatic cancer cells to radiation by modulating cell cycle progression and apoptosis in several pancreatic cancer cell lines. Small interfering RNA-mediated PPARα silencing and PPARα blockade by the antagonist GW6471 abolish the effect of clofibrate on radiosensitization. An in vivo study showed that PANC1 xenografts treated with clofibrate are more sensitive to radiation than untreated xenografts. mRNA profiling by microarray analysis revealed that the expression of PTPRZ1 and Wnt8a, two core components of the β-catenin pathway, is downregulated by clofibrate. Chromatin immunoprecipitation analysis confirmed that clofibrate abrogates the binding of nuclear factor-κB to the PTPRZ1 and Wnt8a promoters, ultimately decreasing Wnt/β-catenin signaling activity, which is associated with radiosensitivity. Overall, we demonstrate that PPARα is overexpressed in pancreatic cancer tissues and clofibrate-mediated PPARα activation sensitizes pancreatic cancer cells to radiation through the Wnt/β-catenin pathway.

23)  Cheng, Rui, et al. “Interaction of PPARalpha with the Wnt pathway, a mechanism for the therapeutic effect of fenofibrate on diabetic nephropathy.” Diabetes (2016): db160426.

24)  Cheng, Rui, et al. “Interaction of PPARα With the Canonic Wnt Pathway in the Regulation of Renal Fibrosis.” Diabetes 65.12 (2016): 3730.

25) Steinhoff, Matthias, et al. “Complete clinical remission of tumor-stage mycosis fungoides after acute extensive skin necroses, granulomatous reaction, and fever under treatment with bexarotene, vorinostat, and high-dose fenofibrate.” Journal of the American Academy of Dermatology 58.5 (2008): S88-S91.

Mycosis fungoides and its variants are a distinct entity with a variable, but well-characterized clinical course. We report on a 51-year-old patient with tumor-stage mycosis fungoides who developed several unusual features such as extensive necrosis of lymphoma lesions, granulomatous reaction, and venular thromboses while under treatment with bexarotene, vorinostat, and high-dose fenofibrate. After surgical removal of skin necroses, the patient recovered and was in complete clinical remission. Possible causal factors such as blastic transformation; hematophagic syndrome; or bacterial, fungal, or viral infection could be excluded. We hypothesize that combination of the high-dose fenofibrate (400 mg) with the retinoid X receptor ligand bexarotene and vorinostat might have induced an increased rate of apoptosis in lymphoma cells in our patient resulting in an extensive release of lymphoma antigens. Augmented antigen release along with changes in local cytokine milieu might have induced macrophage activation and granuloma formation.

ATRA

26) 1405 Combinatorial Use of Bexarotene Plus ATRA for the Treatment of Acute Myeloid Leukemia
Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis  Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster I

27) Vorinostat-Induced Apoptosis in Mantle Cell Lymphoma Is Mediated by Acetylation of Proapoptotic BH3-Only Gene Promoters
Sílvia Xargay-Torrent, Mónica López-Guerra, Ifigènia Saborit-Villarroya, Laia Rosich, Elias Campo, Gaël Roué and Dolors Colomer

28)  Brunmair, Barbara, et al. “Fenofibrate impairs rat mitochondrial function by inhibition of respiratory complex I.” Journal of Pharmacology and Experimental Therapeutics 311.1 (2004): 109-114.

29)   Scatena, Roberto, et al. “Mitochondrial dysfunction by synthetic ligands of peroxisome proliferator activated receptors (PPARs).” IUBMB life 56.8 (2004): 477-482.

30)   Wilk, Anna, et al. “Molecular mechanisms of fenofibrate-induced metabolic catastrophe and glioblastoma cell death.” Molecular and cellular biology 35.1 (2015): 182-198.
Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPARα). FF and several other agonists of PPARα have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPARα-independent mechanism explaining FF’s cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPARα-dependent metabolic switch from glycolysis to fatty acid β-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase–mammalian target of rapamycin–autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells.

31)  The Mitochondria Toxicity of Antihyperlipidemic Agents Bezafibrate and Fenofibrate
Year: 2007  Abstract Number: 0899-P  Author: KOUJI YAMADA
The Mitochondria Toxicity of Antihyperlipidemic Agents Bezafibrate and Fenofibrate Recent epidemiological studies Recent epidemiological studies concerning with lipid intervention trials such as FIELD and BIP studies indicated that antihyperlipidemic agents, fibrates, protect from the onset of type2 diabetes. However, long-term teatment with antihyperlipidemic agents may occur mitochondria (MT) toxicity. Therefore, MT toxicity of antihyperlipidemic agent bezafibrate (BF) was compared with that of fenofibrate (FF), using freshly isolated rat liver MT. FF is known to inhibit strongly the electron transport at complex I in the respiratory chain, but the knowledge on the uncoupling effect on the oxidative phosphorylation is not available. In the present study, the MT toxicity of BF was compared with that of FF with regard to the inhibitiory effect on electron transport system and the uncoupling effect on the oxidative phosphorylation. Rat liver MT were prepared by the usual methods and the respiration was measured by means of oxygen electrode (Iijima Electronics Co. LTD). The effects of BF and FF on H+-ATPase (latent ATPase) and 2,4-dinitrophenol (DNP)-enhanced ATPase (DNP-ATPase) were studied by assaying inorganic phosphate enzymatically released from ATP for detecting both uncoupling effect and inhibitory effect on the energy transfer system.
BF inhibited the NAD-linked electron transport at complex I at significantly higher concentrations than FF, and did not interfere with the succinate-linked respiratory chain. Freshly prepared MT showed no ATPase activity, and the ATPase activity was enhanced by both BF and FF in a dose-dependent manner. These were indicated that the uncoupling effect and the enhancing effect of BF were significantly lower than those of FF. DNP-ATPase was not inhibited by both BF and FF at all, indicating no inhibitory effect on the energy transfer system. From these results, it was concluded that BF as well as FF showed MT toxicity by both fashions of uncoupling effect and electron transport inhibition at complex I. Finally, BF was markedly weaker than FF in the both toxic reactions, suggesting that BF is significantly less toxic than FF in vivo. KOUJI YAMADA, KASUMI TSUNODA, MIO HIRATUKA, KIYOSHI KAWAI, KAZUO KAJITA, TATSUO ISHIZUKA, Gifu, Japan, Ohbu, Japan 0899-P Diabetic Dyslipidemia
Congress: 67th Scientific Sessions (2007)\

32) Panigrahy, Dipak, et al. “PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition.” Proceedings of the National Academy of Sciences 105.3 (2008): 985-990.

33) Biochem Biophys Res Commun. 2018 Jan 29;496(1):70-75. Fenofibrate inhibits mTOR-p70S6K signaling and simultaneously induces cell death in human prostate cancer cells.
Lian X1, Gu J2, Gao B3, Li Y4, Damodaran C5, Wei W3, Fu Y6, Cai L7.
Fenofibrate is the most widely used lipid-lowering drug, but it seems to have anti-tumor effects in several tumor cell lines. However, there are only a few reports on its effects on human prostate cancer cells. Thus, we investigated the anti-proliferative effects of fenofibrate on human prostate cancer cells and potential mechanisms. The methods used include cell viability analysis with an MTT assay, as well as apoptosis and related signaling pathway analyses with flow cytometry and Western blotting. Fenofibrate inhibited PC-3 cell growth in dose- and time-dependent manners. The fenofibrate-induced cell death is predominantly apoptotic death that is mediated by both the caspase-3 activation and apoptosis-inducing factor (AIF) signaling pathways. Fenofibrate also increased the expression of Bad and decreased the expression of Bcl-2 and Survivin. Mechanistically, fenofibrate-induced cell death was associated with decreased p-p70S6K and the mammalian target of rapamycin (mTOR) phosphorylation levels. When further exploring the upstream mediators of mTOR/p70S6K, we found that fenofibrate increased p38 MAPK and AMPK phosphorylation but did not significantly change the phosphorylation levels of PI3K, AKT, and JNK. However, the inhibition of either p38 MAPK or AMPK with their specific inhibitor did not change the effect of fenofibrate-induced cell death. These findings suggested that fenofibrate indeed significantly inhibited the proliferation of PC-3 cells via apoptotic action, which is associated with the inactivation of the mTOR/p70S6K-dependent cell survival pathway. Although the mechanisms by which fenofibrate inactivates this pathway remains unclear, this study reveals great potential for its use for the clinical treatment of prostate cancers.\

34) Lian, Xin, et al. “Anticancer properties of fenofibrate: a repurposing use.” Journal of Cancer 9.9 (2018): 1527.

These studies provide evidence that fenofibrate exerted antitumor effects in several human cancer cell lines, such as breast, liver, glioma, prostate, pancreas, and lung cancer cell lines. Among these studies some have further confirmed the possibility and efficacy of fenofibrate anticancer in xenograft mouse models. In the last part of this review, we also discuss the potential mechanisms of action of fenofibrate based on the available information. Overall, we may repurpose fenofibrate as an anticancer drug in cancer treatment, which urgently need further and comprehensively investigated.

Most recently, PPARα-specific agonists were reported to have anticancer effects in a large number of human cancer types, such as acute myeloid leukemia 14, 15, chronic lymphocytic leukemia 16, and solid tumors, including those of the liver 17, ovary 18, breast, skin, and lungs 19. Furthermore, fenofibrate inhibited the proliferation of cell lines derived from breast and oral tumors, melanoma, lung carcinoma, glioblastoma, and fibrosarcoma in mouse models 19-21.

35)  Saidi, Samir A., et al. “In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer.” Molecular cancer 5.1 (2006): 13.

Fenofibrate, an agonist of PPAR-alpha, in doses above 25 μM, inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells. We show that these effects are potentiated by retinoic acid, an agonist of the retinoid-X-receptor. DNA content analysis shows that G1/S phase progression through the cell cycle is inhibited. Independent Component Analysis of gene microarray experiments demonstrated downregulation of Cyclin D1 (CCND1) and associated changes in cell cycle gene expression. Expression of PPAR-alpha mRNA was reduced by >75% using RNA-interference but this resulted in only minor changes in biological effects. A nude mouse model of endometrial carcinoma was used to investigate the effect of fenofibrate in vivo but failed to show consistent inhibition of tumour growth.  The combination of fenofibrate and retinoic acid is a potent inhibitor of Ishikawa endometrial cancer cell growth in vitro.

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high-dose fenofibrate (400 mg)

Bexarotene is a synthetic retinoic acid agent with potential antineoplastic, chemopreventive, teratogenic and embryotoxic properties. Bexarotene selectively binds to and activates retinoid X receptors (RXRs), thereby inducing changes in gene expression that lead to cell differentiation, decreased cell proliferation, apoptosis of some cancer cell types, and tumor regression.

36)  Steinhoff, Matthias, et al. “Complete clinical remission of tumor-stage mycosis fungoides after acute extensive skin necroses, granulomatous reaction, and fever under treatment with bexarotene, vorinostat, and high-dose fenofibrate.” Journal of the American Academy of Dermatology 58.5 (2008): S88-S91.

Mycosis fungoides and its variants are a distinct entity with a variable, but well-characterized clinical course. We report on a 51-year-old patient with tumor-stage mycosis fungoides who developed several unusual features such as extensive necrosis of lymphoma lesions, granulomatous reaction, and venular thromboses while under treatment with bexarotene, vorinostat, and high-dose fenofibrate. After surgical removal of skin necroses, the patient recovered and was in complete clinical remission. Possible causal factors such as blastic transformation; hematophagic syndrome; or bacterial, fungal, or viral infection could be excluded. We hypothesize that combination of the high-dose fenofibrate (400 mg) with the retinoid X receptor ligand bexarotene and vorinostat might have induced an increased rate of apoptosis in lymphoma cells in our patient resulting in an extensive release of lymphoma antigens. Augmented antigen release along with changes in local cytokine milieu might have induced macrophage activation and granuloma formation.

37) Krempf, M., et al. “Efficacy and safety of micronised fenofibrate in a randomised double-blind study comparing four doses from 200 mg to 400 mg daily with placebo in patients with hypercholesterolemia.” (2000).

The aim of this study was to evaluate the efficacy on LDL-cholesterol (LDL-C) of micronised fenofibrate given for three months at doses ranging from 200 to 400 mg once daily, compared with placebo. A double-blind, randomised, parallel-group, multi-centre trial was performed in four centers of France in 340 hypercholesterolemic patients (163M, 177F) aged 18-75 years. After a 2-3 month single-blind run-in period on placebo and diet, patients with LDL-C greater than or equal to 4.65 mmol/l (180 mg/dl) maintained on the same diet throughout the study were randomly allocated to placebo or to 200, 267, 340 or 400 mg micronised fenofibrate, given once daily with the evening meal for 3 months. LDL-C, total cholesterol (TC), total triglycerides (TG) and apolipoprotein B (Apo B) significantly decreased compared with placebo in all four fenofibrate groups. For all randomised patients, the decrease in the fenofibrate groups ranged from 31.6-38.8% for LDL-C, 24.5-31.9% for TC, 26.7-40.8% for TG, and 27.3-35.0% for Apo B. An increase in HDL-cholesterol of 4.1-8.2% was observed in the fenofibrate groups, but did not reach statistical significance. Lipid values in the placebo group remained unchanged. The therapeutic goal of LDL-C<3.36 mmol/l (130 mg/dl) was reached in 27% in the 200 mg group and increased to 56% in the 300 mg group. There were no major clinical or biological adverse events in the dose interval from 200 mg to 400 mg of micronised fenofibrate per day. This study showed treatment for 3 months with micronised fenofibrate at doses up to 400 mg per day is effective and can reduce LDL-cholesterol up to 30% allowing further evaluation of these doses on longer trials.

ATRA dosing


How I treat acute promyelocytic leukemia  Martin S. Tallman and Jessica K. Altman  Blood 2009 114:5126-5135;

ATRA should be started at the standard dose of  45 mg/m2 per day in divided doses and given emergently, both to resolve the coagulopathy as well as to initiate induction therapy.

Determine your weight or your patient’s weight in kilograms. This is done by dividing weight in pounds by 2.2.

Body Surface Area Dosing

45 mg/square meter
height 71 inches
wt 160 lbs

Dose = 87.19 mg

(4 capsules) 40 mg ATRA twice a day. = 80 mg

Hatake, Kiyohiko, et al. “Rare but important adverse effects of all-trans retinoic acid in acute promyelocytic leukemia and their management.” International journal of hematology 66.1 (1997): 13-19.

Several adverse effects have been reported to occur after clinical application of all-trans retinoic acid (RA) in acute promyelocytic leukemia (APL). Except for severe side effects including retinoic acid syndrome, the mechanism of action of RA on adverse effects remains unclear. Here we describe some rare adverse effects and their management. We reviewed the English literature, and we added our cases of endocrine and metabolic adverse effects, such as hypercalcemia, male infertility, bone marrow necrosis, fibrosis and acute pancreatitis. We also described our cases of thromboembolic events, RA-dependent growth of pathologic cells including Sweet’s syndrome, erythema nodosum, hyperhistaminemia, granulomatous proliferation, and mild cases of pulmonary complications. In addition, we reviewed the efficacy of RA administration for other types of leukemia or myelodysplastic syndrome.

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38)  FREE PDF Retinoic acid inhibits proliferative response CD40 mantle cell lymphoma Guidoboni Massimo Cancer res 2005  Retinoic Acid Inhibits the Proliferative Response Induced by CD40 Activation and Interleukin-4 in Mantle Cell Lymphoma. Massimo Guidoboni,Cancer Res 65 (2005): 587-595.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin’s lymphoma with poor response to therapy and unfavorable prognosis. Here, we show that retinoic acid (RA) isomers significantly inhibit the proliferation of both primary MCL cultures (n = 7) and established cell lines (Granta 519 and SP-53) as shown by [(3)H]thymidine uptake and carboxyfluorescein diacetate succinimidyl ester labeling coupled with cyclin D1 staining. RA induces cell accumulation in G(0)-G(1) together with a marked up-regulation of p27(Kip1) by inhibiting ubiquitination and proteasome-dependent degradation of the protein. The p21(Cip1) inhibitor was also up-regulated by RA in Granta 519 cells, whereas the expression of cyclin D1 is unaffected. Most of RA-induced p27(Kip1) was bound to cyclin D1/cyclin-dependent kinase 4 complexes, probably contributing to the decreased cyclin-dependent kinase 4 kinase activity and pRb hypophosphorylation observed in RA-treated cells. Experiments with receptor-selective ligands indicate that RA receptor alpha cooperates with retinoid X receptors in mediating RA-dependent MCL cell growth inhibition. Notably, RA isomers, and particularly 9-cis-RA, also inhibited the growth-promoting effect induced in primary MCL cells by CD40 activation alone or in combination with interleukin-4. Immunohistochemical analysis showed that significant numbers of CD40L-expressing lymphoid cells are present in lymph node biopsies of MCL patients. These results therefore further strengthen the possibility that triggering of CD40 by infiltrating CD40L+ cells may continuously promote the growth of MCL cells in vivo. On these grounds, our findings that RA inhibits basal MCL proliferation as well as MCL growth-promoting effects exerted by microenvironmental factors make these compounds highly attractive in terms of potential clinical efficacy in this setting.

Note: alitretinoin = 9-cis-retinoic acid = Toctino ®; Basilea Pharmaceuticals, Ltd., United Kingdom,

39)  Singh, Amareshwar TK, et al. “All trans retinoic acid nanodisks enhance retinoic acid receptor mediated apoptosis and cell cycle arrest in mantle cell lymphoma.” British journal of haematology 150.2 (2010): 158-169.

40)  Liposomal Tretinoin Produces Impressive Responses in Refractory B-cell and T-cell Lymphomas February 01, 2001

HOUSTON  Liposomal encapsulated tretinoin (Atragen) is active in relapsed aggressive T-cell and B-cell non-Hodgkin’s lymphomas (NHL) as well as in cutaneous T-cell lymphomas (CTCL), and strikingly effective in patients with primary refractory disease. Andreas H. Sarris, MD, PhD, associate internist and associate professor of medicine at the University of Texas M. D. Anderson Cancer Center in Houston, reported these results in a poster presentation. Liposomal tretinoin is more active than the oral formulation when tested against lymphoma cell lines and also down regulates expression of bcl-2, Dr. Sarris said.

41) Sep 1, 2017 – Break Through Treatment for Mantle Cell Lymphoma.
Breakthrough Treatment for Mantle Cell Lymphoma Nahla A M Hamed*
Professor of Hematology, Faculty of Medicine, Alexandria University, Egypt

the combination of bortezomib and a retinoid compound, fenretinide is synergistically cytotoxic against MCL lines and warrants further evaluation in vivo and in clinical trials.

In addition, the combination of anti-Mcl-1 lipidoid nanoparticles with other forms of targeted therapy offers hope for reducing or replacing cytotoxic chemotherapy as standard treatment for MCL that over express Mcl-1.

The combination of bortezomib and a retinoid compound, fenretinide is synergistically cytotoxic against MCL lines. This appears to be mediated by modulation of I?K and
I?Ba, cell cycle dysregulation and apoptotic cell death. These combinations have moderate toxicity profile and warrants further evaluation in vivo and in clinical trials [16].

E. Lipidoid nanoparticles siRNA therapy targeting Mcl-1 has potential as a new treatment modality for MCL that over express Mcl-1. The combination of anti-Mcl-1 lipidoid nanoparticles with other forms of targeted therapy offers hope for reducing or replacing cytotoxic chemotherapy as standard treatment for   MCL

43)   Anticancer Drugs. 2015 Oct;26(9):974-83.
Bortezomib and fenretinide induce synergistic cytotoxicity in mantle cell lymphoma through apoptosis, cell-cycle dysregulation, and I?Ba kinase downregulation.
Cowan AJ1, Frayo SL, Press OW, Palanca-Wessels MC, Pagel JM, Green DJ, Gopal AK.
Author information  aClinical Research Division, Fred Hutchinson Cancer Research Center bDepartment of Medicine, Division of Medical Oncology, University of Washington cSeattle Genetics Inc., Seattle, Washington, USA.

Mantle cell lymphoma (MCL) remains incurable for most patients, and proteasome inhibitors like bortezomib induce responses in a minority of patients with relapsed disease. Fenretinide is a retinoid that has shown preclinical activity in B-cell lymphomas. We hypothesized that these agents could yield augmented antitumor activity. MCL lines (Granta-519, Jeko-1, and Rec-1) were treated with escalating concentrations of bortezomib and fenretinide singly and in combination. Cytotoxicity was assessed using the MTT assay. Flow cytometric methods were used to assess apoptosis and necrosis, with annexin V-FITC/propidium iodide staining, and G1 and G2 cell-cycle changes were assessed by DAPI staining. Changes in cyclin D1, cyclin B, I?Ba, and IKKa expressions were quantified by western blotting. Cytotoxicity was mediated through apoptosis; both agents showed observed versus expected cytotoxicities of 92.2 versus 55.1% in Granta-519, of 87.6 versus 36.3% in Jeko-1, and of 63.2 versus 29.8% in Rec-1. Isobolographic analysis confirmed synergy in Jeko-1 and Rec-1 cell lines. Bortezomib induced G2-phase arrest, with a 1.7-fold increase compared with control, and fenretinide resulted in G1-phase arrest, with an increase of 1.3-fold compared with control. In the combination, G2-phase arrest predominated, with a 1.4-fold increase compared with control, and there was reduced expression of cyclin D1 to 24%, cyclin B to 52 and 64%, cyclin D3 to 25 and 43%, I?Ba to 23 and 46%, and I?Ba kinase to 34 and 44%. Bortezomib and fenretinide exhibit synergistic cytotoxicity against MCL cell lines. This activity is mediated by I?Ba kinase modulation, decreased cyclin expression, cell cycle dysregulation, and apoptotic cell death.

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Fenofibrate Anti-Cancer Drug
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Fenofibrate Anti-Cancer Drug
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About Jeffrey Dach MD

Medical Director of TrueMedMD, a Clinic in Davie Florida specializing in Bioidentical Hormones and Natural thyroid. Office address 7450 Griffin Road Suite 190, Davie, Florida 33314 telephone 954-792-4663