Cancer Stem Cells Natural Therapies Part Two

Bee_propolis_CAPE_Anticancer_Beta_Catenin_WNT_TCFCancer Stem Cells Natural Therapies
Part Two

This article is part two, for part one, click here.

In part one, we discussed  natural therapies targeting cancer stem cells.  In addition, we discussed the anti-parasitic drug, Ivermectin, which has remarkable anticancer stem cell activity via inhibition of the WNT/TCF/Beta-Catenin Pathway.

CAPE Inhibits Cancer Stem Cells

Another such potent anti-cancer natural agent is a substance is found in bee propolis,  known by the acronym CAPE which is short for Caffeic Acid Phenethyl Ester, (see below image courtesy of Pengxuan Zhang et al. Molecules 2014).(12)

Chemical structure caffeic acid phenethyl ester (CAPE) Bee PropolisDr Omene in 2012 reported that CAPE inhibits breast cancer in vitro  and in vivo mouse xenograft models.  CAPE also inhibited the breast cancer stem cells.(4)  The CAPE inhibited  gene expression for NF-κB, EGFR, and VEGF. (4)

Dr  Xiang reported in 2006, that CAPE from bee propolis (Caffeic acid phenethyl ester) induces apoptosis of colon cancer cells via suppression of  the Beta-Catenin/T-cell factor signaling pathway. (5).  The authors reported CAPE treated cancer cells had decreased total beta-Catenin protein, and decreased nuclear beta-catenin.  In addition, there was CAPE treatment reduced expression of cyclin D1 and c-myc, showing that CAPE is an excellent inhibitor of  Beta-Catenin/TCF in colon cancer cells.  In addition CAPE down regulates Nuclear Factor Kappa Beta.(1-12)

Down Regulation of BetaCatenin Signalling

Fig 7A He Yu-Jun Inhibitory effect of caffeic acid phenethyl ester beta-catenin downregulation 2006Above image shows green color for β-catenin localization in colon cancer (SW480) cells.  Compared to untreated cancer cells (Left Fig A), the cancer cells treated with CAPE (Right Image B) (bee propolis) show decreased β-catenin protein in nucleus and cytoplasm, and concurrently increased its accumulation of green Beta Catenin on the surface of cell membrane.  From Figure 7A/B He 2006 (6) He, Yu-Jun, et al. “Inhibitory effect of caffeic acid phenethyl ester on the growth of SW480 colorectal tumor cells involves beta-catenin associated signaling pathway down-regulation.” World Journal of Gastroenterology 12.31 (2006): 4981.

Blocking p21 PAK-1 Pathway

CAPE_Curcumin_Blocks_PAK1_anti_cancerDr Hiroshi Maruta reports in 2011 that CAPE in Bee propolis is an effective PAK-1 blocker and anti-cancer agent,  effective for suppressing neurofibromas and meningiomas in neurofibromatosis patients.(17)  It was also effective for glioma and pancreatic cancer cases without any side effects.(17)  Left image Similar Chemical Structures of CAPE and Curcumin courtesy of Dr. H. Maruto (17).

PAK-1 Blockers Also Promote Hair Growth

In their article in 2016 Phytotherapy Research, Drs  Nguyen, Taira, and Maruta report that herbal Pak-1 Blockers such as Bee Propolis and Bitter Melon not only inhibit cancer cells, they also promote hair growth.  Results are better than Minoxidil.(11)

Conclusion: Bee Propolis contains ingredients such as CAPE with potent anticancer activity by virtue of down-regulation of the Beta Catenin/WNT pathway.  CAPE also blocks the oncogenic p-21 PAK-1 pathway. (17)

Buy Manuka Honey Bee Propolis on Amazon

Articles with Related Interest:

Ivermectin, Anticancer Wonder Drug

Targeting Cancer Stem Cells with NonToxic Therapies

Artemisinin our Ultimate Cancer Weapon a Gift from China

Jeffrey Dach MD
7450 Griffin Road Suite 180
Davie, Fl 33314

Links and References

bee propolis  caffeic acid phenethyl ester


Patel, Seema. “Emerging Adjuvant Therapy for Cancer: Propolis and its Constituents.” Journal of dietary supplements 13.3 (2016): 245-268.

Cancer inhibition by propolis is so far the most startling finding. Cancer is a multifactorial disease, triggered by genetic aberrations and environmental mutagens and their hostile interactions. Antitumor properties of propolis have been attributed to the bolstered antioxidant status, augmented immune-surveillance, suppression of proliferation, reduction in the cancer stem cell populations, blockage of specific oncogene signalling pathways, anti-angiogenesis, modulation of the tumour microenvironment, valorization of chemotherapeutics and alleviation of side effects induced by drugs (Meneghelli, Joaquim, Flix, Somensi, Tomazzoli and da Silva, 2013).

It was observed that the Chinese red propolis and CAPE in particular showed strong suppressive effects against VEGF-induced angiogenesis

2015  free pdf

2) Murtaza, Ghulam, et al. “Possible molecular targets for therapeutic applications of caffeic acid phenethyl ester in inflammation and cancer.” Journal of Food and Drug Analysis 23.1 (2015): 11-18.

At a dose of approximately 80 mM, CAPE generally inhibits the activated nuclear factor-kB (NF-kB) and other transcription factors via suppressing their binding with DNA

It is noteworthy to mention here that CAPE does not influence other tissues of body, and thus the usage of this natural anticancer agent is free of side effects with effective chemopreventive feature

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3) Armutcu, Ferah, et al. “Therapeutic potential of caffeic acid phenethyl ester and its anti-inflammatory and immunomodulatory effects (Review).” Experimental and therapeutic medicine 9.5 (2015): 1582-1588.

CAPE is a potent and a specific inhibitor of nuclear factor-κB (NF-κB) activation, and this may provide the molecular basis for its multiple anti-inflammatory and immunomodulatory activities

CAPE suppresses NF-κB activation by inhibiting the interaction between NF-κB proteins and DNA

CAPE inhibits Breast Cancer Stem Cells

Omene, Coral O., Jing Wu, and Krystyna Frenkel. “Caffeic Acid Phenethyl Ester (CAPE) derived from propolis, a honeybee product, inhibits growth of breast cancer stem cells.” Investigational new drugs 30.4 (2012): 1279-1288.

Cancer stem cells (CSC) are chemoresistant and implicated in tumor recurrence, metastasis and high patient mortality; thus substances impairing CSC activity, could be invaluable as novel cancer therapeutics. We previously showed that CAPE (caffeic acid phenethyl ester), a component of propolis, a honeybee product, inhibits growth of MDA-MB-231 (MDA-231) cells, mdr gene expression, NF-κB, EGFR, and VEGF. We hypothesized that CAPE also acts by interfering with CSC-mediated effects. We isolated breast CSC (bCSC) from MDA-231 cells, a model of human triple-negative breast cancer, and mouse xenografts. bCSC grow as mammospheres (MMS) and when dissociated into single cells, form MMS again, a sign of self-renewal. bCSC exhibited the characteristic CD44(+)/CD24(-/low) phenotype and generated progenitors in the presence of serum, a CSC trait responsible for regenerating tumor mass. CAPE caused dose-dependent bCSC self-renewal inhibition and progenitor formation. Clonal growth on soft agar was inhibited dose-dependently, but apoptosis was not induced as determined by Annexin-V/PI assay. Instead, bCSC were noted to significantly progress from a quiescent cell cycle state in G0/G1 (82%), S phase (12%) to a cycling state with an increase in S phase (41%) and subsequent decrease in G0/G1 (54%). Treatment of bCSC with CAPE (4.5-days) decreased CD44 levels by 95%, while another cell population containing 10-100-fold lower CD44 content concurrently increased. Results suggest that CAPE causes pronounced changes in bCSC characteristics manifested by inhibition of self renewal, progenitor formation, clonal growth in soft agar, and concurrent significant decrease in CD44 content, all signs of decreased malignancy potential.

our results suggest that CAPE causes pronounced changes in breast cancer stem cell characteristics manifested by inhibition of self renewal, inhibition of clonal expansion in soft agar, and decrease in CD44 content, all signs of decreased potential for malignancy. Further, CAPE induces an increase in the cycling state of the bCSCs, potentially making them more susceptible to chemotherapeutic agents if used in combination.

Anticancer Drugs. 2006 Aug;17(7):753-62.
Caffeic acid phenethyl ester induces growth arrest and apoptosis of colon cancer cells via the beta-catenin/T-cell factor signaling.
Xiang D1, Wang D, He Y, Xie J, Zhong Z, Li Z, Xie J.

Caffeic acid phenethyl ester, an active component of propolis, has been implicated in the regulation of cell growth and apoptosis, although the exact mechanism of this activity has not been elucidated. In this study, we explored the effects of caffeic acid phenethyl ester on growth, cell cycle, apoptosis and beta-catenin/T-cell factor signaling in human colon cancer cells. Using two human sporadic colon cancer cell lines (HCT116 and SW480), we assayed for cell growth inhibition, cell cycle and apoptosis induction. We also assayed for beta-catenin and downstream target genes (cyclin D1 and c-myc) mRNA and protein expression by reverse transcriptase-polymerase chain reaction and Western blot analysis. Beta-catenin localization was detected by indirect immunofluorescence. Beta-catenin/T-cell factor transcriptional activity was determined by transient transfection and reporter gene assay. Caffeic acid phenethyl ester completely inhibited growth, and induced G1 phase arrest and apoptosis in a dose-dependent manner in both HCT116 and SW480 cells. Treatment of human colon cancer cells with apoptotic concentrations of caffeic acid phenethyl ester resulted in a dose-dependent and time-dependent loss of total beta-Catenin protein, associated with decreased nuclear beta-catenin. Caffeic acid phenethyl ester reduced the expression of cyclin D1 and c-myc in a dose-dependent and time-dependent manner. We proved that caffeic acid phenethyl ester markedly suppressed the transcriptional activity of beta-catenin/T-cell factor in both HCT116 and SW480 cells depending on the concentration of caffeic acid phenethyl ester. These results indicate that caffeic acid phenethyl ester is an excellent inhibitor of beta-catenin/T-cell factor signaling in colon cancer cell lines and suggest that caffeic acid phenethyl ester merits further study as an agent against colorectal cancers.

Nice image figute 7 shows cell localalization of Beta Cateninin before and after bee propolis

He, Yu-Jun, et al. “Inhibitory effect of caffeic acid phenethyl ester on the growth of SW480 colorectal tumor cells involves beta-catenin associated signaling pathway down-regulation.” World Journal of Gastroenterology 12.31 (2006): 4981.


Ye, Diana Zi, and Jeffrey Field. “PAK signaling in cancer.” Cellular logistics 2.2 (2012): 105-116.
Transformation of a normal cell to a cancer cell is caused by mutations in genes that regulate proliferation, apoptosis, and invasion. Small GTPases such as Ras, Rho, Rac and Cdc42 orchestrate many of the signals that are required for malignant transformation. The p21-activated kinases (PAKs) are effectors of Rac and Cdc42. PAKs are a family of serine/threonine protein kinases comprised of six isoforms (PAK1–6), and they play important roles in cytoskeletal dynamics, cell survival and proliferation. They act as key signal transducers in several cancer signaling pathways, including Ras, Raf, NFκB, Akt, Bad and p53. Although PAKs are not mutated in cancers, they are overexpressed, hyperactivated or amplified in several human tumors and their role in cell transformation make them attractive therapeutic targets. This review discusses the evidence that PAK is important for cell transformation and some key signaling pathways it regulates. This review primarily discusses Group I PAKs (PAK1, PAK2 and PAK3) as Group II PAKs (PAK4, PAK5 and PAK6) are discussed elsewhere in this issue (by „Minden).

PAKs are overexpressed and/or hyperactivated in several human tumors such as breast cancer, neurofibromatosis, colon cancer and lung cancer. They maintain cell transformation by promoting a number of hallmark processes including cell proliferation, survival, motility and angiogenesis

PAK Activation and Amplification in Cancer

There is little evidence for cancer cells having activating mutations in PAK genes although a mutation was found in the kinase domain of PAK4 (E329K) in a colorectal tumor sample. It is not known if the mutation affects kinase activity.3 However, PAK family members are amplified, overexpressed or hyperactivated in a number of human tumors. PAK1 is the isoform most commonly overexpressed but other family members, most often PAK4 is overexpressed in specific cancers (Table 1). PAK4, for example, is overexpressed in 75% of the NCI 60 cell line panel and a dominant negative mutant will block cell transformation of a colon cancer cell line.4

Several distinct molecular mechanisms cause aberrant PAK signaling in cancer, including gene amplification and alteration of upstream regulators. Both PAK1 and PAK4 are localized to genomic regions, which are frequently amplified in cancer cells. The PAK1 gene is localized within the 11q13 region, and 11q13.5-q14 amplifications involving the PAK1 locus are found in bladder, ovary and breast cancer.5-8 PAK4 localizes to another amplicon, 19q13.2, and PAK4 gene amplification has been found in colorectal and pancreatic cancers.3,9

Recently, PAK2 has been shown to be essential for the activation of proliferation signals Wnt/β-catenin signaling in schwannoma cells, and depletion of PAK2 suppressed active β-catenin, c-myc and cyclin D1.53 In NF2 tumors, loss of PAK activity, however, did not reduce Erk or Akt activity, two signaling proteins that are thought to mediate PAK function in NF1.52 Together, these studies suggest that PAK is a major player underlying Schwann cell transformation and an attractive target for therapeutics in both NF1 and NF2. There are multiple signaling pathways that PAK regulates in Schwann cells and the signals may differ between NF1 and NF2.

Overexpression of PAK1 is observed in 70% of colon cancer samples and is correlated with several signaling pathways including, Wnt, Erk and Akt pathways. Reduction of PAK1 expression decreased cell proliferation, migration/invasion, and survival. Rac1/PAK1 cascade controls β-catenin S675 phosphorylation and its activation in colon cancer cells. Downregulation of PAK1 in colon cancer cells reduces the β-catenin levels and cell proliferation. PAK1 also directly phosphorylated β-catenin at Ser675, leading to more stable and transcriptional active β-catenin.57 Erk and Akt, downstream targets of PAK1 are involved in colon cancer progression. PAK inhibition alone is equivalent to the dual inhibition of Erk and Akt, whereas inactivation of either the Erk or Akt pathway alone partially inhibited cell migration/invasion and survival and had no effect on proliferation. Thus, in at least this one case, instead of simultaneously inhibiting both Erk and Akt, PAK1 may be a convergence point for therapy.58

Lung cancer
Lung cancer, although not as well established as other cancers, is emerging as a tumor depends on PAK1 signaling. A mouse model for Ras-induced lung cancers is highly sensitive to Rac inhibition, suggesting that lung cancers may be dependent on PAK.59 PAK1 is expressed strongly in the nucleus and cytoplasm of squamous nonsmall cell lung carcinomas (NSCLCs).8 Finally, selective inhibition of PAK1 but not PAK2 delayed cell-cycle progression in vitro and in vivo.8


Propolis blocks PAK1

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Combination of immunoprecipitation (IP)-ATP_Glo kinase assay and melanogenesis for the assessment of potent and safe PAK1-blockers in cell culture.
Nguyen BC1, Be Tu PT, Tawata S, Maruta H.
Cucurbitacin I (CBI) is a triterpene from a bitter melon called Goya grown in Okinawa, Japan, and directly inhibits both the Tyr-kinase JAK2 and the G protein RAC, leading to the inactivation of PAK1 (RAC/CDC42-activated kinase 1). Bio 30, a propolis produced in New Zealand, contains CAPE (caffeic acid phenethyl ester) as the major anti-cancer ingredient which directly down-regulates RAC, leading to the inactivation of PAK1. Since PAK1 is essential for the growth of RAS cancer cells such as A549 cell line which carry an oncogenic K-RAS mutant, and the melanogenesis in skin cells, here using these PAK1-blockers as model compounds, we introduce a new approach to the quick assessment of PAK1-blockers in cell culture. First, combining the immuno-precipitation (IP) of PAK1 from cell lysate and the in vitro ATP_Glo kinase assay kit (called “Macaroni-Western” assay), we confirmed that both CBI and Bio 30 inactivate PAK1 in A549 lung cancer cells in 24 h, and inhibit their PAK1-dependent growth in 72 h. Furthermore, we verified that CBI inhibits the PAK1/PAK4-dependent melanogenesis in melanoma cells by far more than 50%, while Bio 30 inhibits the melanogenesis only by 50%, with only a merginal effect on their growth per se. Since the “Macaroni-Western” kinase assay and melanogenesis are both rather simple and quick, the combination of these two cell culture assays would be highly useful for selecting both “potent” (highly cell-permeable) and “safe” (non-toxic) natural or synthetic PAK1-blockers.

Cucurbitacin I (CBI) was purified from bitter melon called “Goya” by our own laboratory as previously described (13).

Bio 30, a CAPE (caffeic acid phenethyl ester)-based propolis (tincture) from New Zealand was obtained from Manuka Health in Auckland. The content of major ingredients in Bio 30 was described in detail previously (14).

Phytother Res. 2009 Mar;23(3):423-7. doi: 10.1002/ptr.2658.
Artepillin C (ARC) in Brazilian green propolis selectively blocks oncogenic PAK1 signaling and suppresses the growth of NF tumors in mice.
Messerli SM1, Ahn MR, Kunimasa K, Yanagihara M, Tatefuji T, Hashimoto K, Mautner V, Uto Y, Hori H, Kumazawa S, Kaji K, Ohta T, Maruta H.
There are mainly three types of propolis whose major anticancer ingredients are entirely different: (1) CAPE (caffeic acid phenethyl ester)-based propolis in Europe, Far East and New Zealand, (2) artepillin C (ARC)-based Brazilian green propolis and (3) Brazilian red propolis. It was shown previously that NF (neurofibromatosis)-associated tumors require the kinase PAK1 for their growth, and CAPE-based propolis extracts such as Bio 30 suppress completely the growth of NF tumors in vivo by blocking PAK1 signaling. Also it was demonstrated that ARC suppresses angiogenesis, suggesting the possibility that ARC also blocks oncogenic PAK1 signaling. Here it is shown for the first time that both ARC and green propolis extract (GPE) indeed block the PAK1 signaling selectively, without affecting another kinase known as AKT. Furthermore, it was confirmed that ARC as well as GPE suppress almost completely the growth of human NF tumor xenografts in mice, as does Bio 30. These results suggest that both CAPE-based and ARC-based propolis extracts are natural anti-PAK1 remedies and could be among the first effective NF therapeutics available on the market. Since more than 70% of human cancers such as breast and prostate cancers require the kinase PAK1 for their growth, it is quite possible that GPE could be potentially useful for the treatment of these cancers, as is Bio 30.

Phytother Res. 2014 May;28(5):656-72. doi: 10.1002/ptr.5054. Epub 2013 Aug 14.
Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity.
Maruta H1.
Over 35 years research on PAKs, RAC/CDC42(p21)-activated kinases, comes of age, and in particular PAK1 has been well known to be responsible for a variety of diseases such as cancer (mainly solid tumors), Alzheimer’s disease, acquired immune deficiency syndrome and other viral/bacterial infections, inflammatory diseases (asthma and arthritis), diabetes (type 2), neurofibromatosis, tuberous sclerosis, epilepsy, depression, schizophrenia, learning disability, autism, etc. Although several distinct synthetic PAK1-blockers have been recently developed, no FDA-approved PAK1 blockers are available on the market as yet. Thus, patients suffering from these PAK1-dependent diseases have to rely on solely a variety of herbal therapeutics such as propolis and curcumin that block PAK1 without affecting normal cell growth. Furthermore, several recent studies revealed that some of these herbal therapeutics significantly extend the lifespan of nematodes (C. elegans) and fruit flies (Drosophila), and PAK1-deficient worm lives longer than the wild type. Here, I outline mainly pathological phenotypes of hyper-activated PAK1 and a list of herbal therapeutics that block PAK1, but cause no side (harmful) effect on healthy people or animals.

propolis and curcumin that block PAK1 without affecting normal cell growth.

Phytother Res. 2016 Jan;30(1):120-7.  Artepillin C and Other Herbal PAK1-blockers: Effects on Hair Cell Proliferation and Related PAK1-dependent Biological Function in Cell Culture.  Nguyen BC1, Taira N1, Maruta H2, Tawata S3.

PAK1 (RAC/CDC42-activated kinase 1) is the major oncogenic kinase, and a number of herbal PAK1-blockers such as propolis and curcumin have been shown to be anti-oncogenic and anti-melanogenic as well as anti-alopecia (promoting hair growth). Previously, we found several distinct PAK1-inhibitors in Okinawa plants including Alpinia zerumbet (alpinia). Thus, here, we tested the effects of these herbal compounds and their derivatives on the growth of cancer or normal hair cells, and melanogenesis in cell culture of A549 lung cancer, hair follicle dermal papilla cell, and B16F10 melanoma. Among these herbal PAK1-inhibitors, cucurbitacin I from bitter melon (Goya) turned out to be the most potent to inhibit the growth of human lung cancer cells with the IC50 around 140 nM and to promote the growth of hair cells with the effective dose around 10 nM. Hispidin, a metabolite of 5,6-dehydrokawain from alpinia, inhibited the growth of cancer cells with the IC50 of 25 μM as does artepillin C, the major anti-cancer ingredient in Brazilian green propolis. Mimosine tetrapeptides (MFWY, MFYY, and MFFY) and hispidin derivatives (H1-3) also exhibited a strong anti-cancer activity with the IC50 ranging from 16 to 30 μM. Mimosine tetrapeptides and hispidin derivatives strongly suppressed the melanogenesis in melanoma cells.ropolis  caffeic acid phenethyl ester

12) Zhang, Pengxuan, et al. “Bioactivity and chemical synthesis of caffeic acid phenethyl ester and its derivatives.” Molecules 19.10 (2014): 16458-16476.

13) Int J Biochem Cell Biol. 2016 Feb;71:111-8. doi: 10.1016/j.biocel.2015.12.012. Epub 2015 Dec 25.
Caffeic acid phenethyl ester: Inhibition of metastatic cell behaviours via voltage-gated sodium channel in human breast cancer in vitro.
Fraser SP1, Hemsley F2, Djamgoz MB3.
Caffeic acid phenethyl ester, derived from natural propolis, has been reported to have anti-cancer properties. Voltage-gated sodium channels are upregulated in many cancers where they promote metastatic cell behaviours, including invasiveness. We found that micromolar concentrations of caffeic acid phenethyl ester blocked voltage-gated sodium channel activity in several invasive cell lines from different cancers, including breast (MDA-MB-231 and MDA-MB-468), colon (SW620) and non-small cell lung cancer (H460). In the MDA-MB-231 cell line, which was adopted as a ‘model’, long-term (48h) treatment with 18μM caffeic acid phenethyl ester reduced the peak current density by 91% and shifted steady-state inactivation to more hyperpolarized potentials and slowed recovery from inactivation. The effects of long-term treatment were also dose-dependent, 1μM caffeic acid phenethyl ester reducing current density by only 65%. The effects of caffeic acid phenethyl ester on metastatic cell behaviours were tested on the MDA-MB-231 cell line at a working concentration (1μM) that did not affect proliferative activity. Lateral motility and Matrigel invasion were reduced by up to 14% and 51%, respectively. Co-treatment of caffeic acid phenethyl ester with tetrodotoxin suggested that the voltage-gated sodium channel inhibition played a significant intermediary role in these effects. We conclude, first, that caffeic acid phenethyl ester does possess anti-metastatic properties. Second, the voltage-gated sodium channels, commonly expressed in strongly metastatic cancers, are a novel target for caffeic acid phenethyl ester. Third, more generally, ion channel inhibition can be a significant mode of action of nutraceutical compounds.

14) Silva-Carvalho, Ricardo, et al. “Antitumoural and antiangiogenic activity of Portuguese propolis in in vitro and in vivo models.” Journal of Functional Foods 11 (2014): 160-171. Silva_Carvalho Rl_2014_Antitumoural propolis

15) Lin, Hui-Ping, et al. “Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21Cip1 and p27Kip1.” Oncotarget 6.9 (2015): 6684.
Caffeic acid phenethyl ester (CAPE) is a main bioactive component extracted from honeybee hive propolis. CAPE is a well known NF-κB inhibitor at concentrations of 50 μM to 80 μM by preventing the translocation of p65 unit of NF-κB and the binding between NF-κB and DNA [17].
Our study suggested that CAPE treatment can efficiently induced G1 or G2/M cell cycle arrest, cellular and growth inhibition in CRPC cells via inhibition of Skp2 as well as induction of p21Cip1, p27Kip1, and p53 in CRPC cell lines. Our finding implied that CAPE treatment might be a potential therapy for patients with CRPC.

16) Natarajan K, Singh S, Burke TR, Jr, Grunberger D, Aggarwal BB. Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa, B. Proc Natl Acad Sci U S A. 1996;93:9090–5.
Thus, overall our results demonstrate that CAPE is a potent and a specific inhibitor of NF-kappa B activation and this may provide the molecular basis for its multiple immunomodulatory and antiinflammatory activities.

17) Maruta, Hiroshi. “Effective neurofibromatosis therapeutics blocking the oncogenic kinase PAK1.” Drug discoveries & therapeutics 5.6 (2011): 266-278. Maruta Hiroshi neurofibromatosis therapeutics blocking PAK1 Drug discoveries therapeutics 2011

For 3-4 years since mid-2007, we have been conducting human trials of ”Bio 30” (alcohol-free liquid) containing 250 mg of extract/mL, mainly for NF patients world-wide, and the effective minimum daily dose of ”Bio 30” (25 mg/kg = 1 mL/10 kg) has stopped the growth of their tumors in most cases of both NF1 and NF2 patients as well as glioma and pancreatic cancer patients, without any side effect (22). Furthermore, in three NF1 (dermal
neurofibroma) cases, tumors completely disappeared in a month.

Also at least in three cases of NF2 (both schwannoma and meningioma) and one glioma case, these brain tumors shrank by more than 50% in 2-3
years. In two pancreatic cancer cases, both early and metastasized ”terminal” cancers completely disappeared in one year

As shown in Figure 4, CAPE in propolis and curcumin, the spicy yellow ingredient in Indian curry (Turmeric powder) are structurally very similar, and as expected, both polyphenols were found to block PAK1 and activate
AMPK (6,32-34). Like CAPE, curcumin suppresses the growth of many PAK1-dependent cancer cells in vitro,

Ivermectin – Ivermectin (3-5 mg/kg, daily) almost completely suppresses the growth of a few distinct human cancers such as melanoma

anti- PAK1 compounds such as CAPE, curcumin, apigenin, berberine, resveratrol, emodin, salidroside, capsaicin/ capsiate, OSU-03012, GW2974, metformin, etc. are known to activate the tumor suppressing kinase AMPK
(see Table 2).

18) Bee Propolis is Venomous to Cancer Cells  Ryan Sternagel February 16, 2016 The Many Ways Bee Propolis Can Fight Many Cancers


19) Varghese, Elizabeth, et al. “The “yin and yang” of natural compounds in anticancer therapy of triple-negative breast cancers.” Cancers 10.10 (2018): 346.

nice discussion of oncogenic pathways in TNBC

We have linked the anticancer potential of plant-derived natural compounds (luteolin, chalcones, piperine, deguelin, quercetin, rutin, fisetin, curcumin, resveratrol, and others) to their ability to target multiple dysregulated signaling pathways (such as the Wnt/β-catenin, Notch, NF-κB, PI3K/Akt/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and Hedgehog) leading to suppression of cell growth, proliferation, migration, inflammation, angiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, and activation of apoptosis in TNBCs. Plant-derived compounds in combination with classical chemotherapeutic agents were more efficient in the treatment of TNBCs, possibly with lesser side effects.

In TNBCs, six major cell signaling pathways are de-regulated: (1) Wnt, (2) Notch, (3) NF-κB, (4) PI3K/Akt/mTOR, (5) MAPK, and (6) Hedgehog pathways

This Wnt-receptor association leads to GSK-3β inactivation, as well as release of β-catenin from the death complex and its translocation into the nucleus, driving the expression of T-cell factor/lymphoid enhancing factor (TCF/LEF) target genes. This subsequently leads to gene translation and expression of proteins (such as c-Myc, cyclin D1, COX2, VEGF, MMP7 and WISP3) [41] (Figure 1) that regulate cell cycle, migration, proliferation, differentiation, and survival [39,42]. GSK-3β also mediates other major signaling pathways such as the Notch pathway, the NF-κB signaling pathway, the PI3K pathway, and the Hedgehog pathway [43].

Here, we highlight the potential of using phytochemicals (luteolin, chalcones, piperine, deguelin, quercetin, rutin, fisetin, resveratrol, curcumin, maximiscin, cyclopamine, capsaicin, and genistein) in the treatment of TNBCs and provide an in-depth analysis of their mechanisms of action.


Quercetin (Figure 2E and Figure 3), a flavanol, has antioxidant, anti-inflammatory, and anticancer properties [154,168]. Quercetin-mediated growth inhibition and activation of pro-apoptotic mechanisms were observed in different cancer cell models, including breast cancers [222,223,224]. Quercetin related, suppression of cancer cell proliferation operates via inhibition of intracellular signaling pathways such as PI3K, EGFR and Her2/neu, while the induction of cancer cell apoptosis is modulated via inhibition of the survival signaling pathways (Akt, NF-κB) or regulatory molecules associated with cell apoptosis (p53, Bcl-2 family, FasL) [222]. Quercetin treatment induces downregulation of anti-apoptotic Bcl-2 and upregulation of pro-apoptotic Bax, increases the levels of cytochrome C levels and cleaved forms of caspase-9, caspase-3 and PARP-1 [225].

Quercetin-mediated activation of caspase-3, -8 and -9, increase in levels pro-apoptotic protein Bax, decrease in levels of anti-apoptotic protein Bcl-2 and release of apoptosis-inducing factor (AIF) from mitochondria and its subsequent translocation into the nucleus correlated with the dose- and time-dependent G2/M cell cycle arrest and apoptosis (more cells in the sub-G1 phase) in quercetin treated MDA-MB-231 TNBC cells [226]. Reportedly, the anti-proliferative effects of quercetin through G2/M cell cycle arrest and apoptosis in human luminal androgen receptor-positive MDA-MB-453 TNBC cells is mediated through increased Bax expression; cleaved caspase 3 and PAR expression; and decreased Bcl-2 expression [227]. In a C3(1)/SV40 Tag breast cancer mouse model, quercetin administration was well tolerated and reduced the number of tumor cells and their volume in a dose-dependent manner [228].

In MDA-MB-231 cells, quercetin treatment caused a JNK pathway-mediated increase in the protein level, transcriptional activity, and nuclear translocation of pro-apoptotic Foxo3a, which in turn activated cell death mechanisms via p53, p21, and GADD45 signaling [222]. Additionally, quercetin treatment also increased the expression of Fas ligand (FasL, a pro-apoptotic factor that activates Fas receptor-mediated apoptosis) mRNA [222]. These quercetin treatment-associated pro-apoptotic events reduced viability, induced apoptosis, and caused S-phase and G2/M cell cycle arrest, along with a reduction in cells in the G0/G1 phase of the cell cycle [222].

Quercetin treatment was associated with a significant growth-inhibitory effect in MDA-MB-231 and MDA-MB-157 TNBC cells [177]. Quercetin treatment in these TNBC cells induced morphological alterations, DNA fragmentation, and caspase-3 activation, in addition to decreased protein expression of lipogenic enzyme FasN, anti-apoptotic Bcl-2, β-catenin, and reduced nuclear accumulation of β-catenin, indicating a quercetin-mediated inhibition of the Wnt/β-catenin signaling in TNBCs [177]. Quercetin administration also significantly decreased MDA-MB-231 breast tumor xenograft growth in mice [177]. Quercetin treatment-associated reduction in nuclear translocation of β-catenin and subsequent downregulation of Wnt/β-catenin signaling-related genes such as cyclin D1, c-Myc at the mRNA and protein level led to a decrease in growth, survival, migration, and altered morphology in MDA-MB-231 and MDA-MB-468 TNBC cells [229]. Quercetin treatment-associated decrease in the phosphorylation of Akt could have contributed to the decrease in the phosphorylation of GSK-3β, thereby indicating that quercetin can target multiple signaling pathways simultaneously [229]. Furthermore, quercetin treatment decreased the levels of vimentin (increased levels support EMT) and increased the levels of E-cadherin (decreased levels supports EMT) indicating that quercetin can inhibit EMT and metastasis [229].

Quercetin treatment sensitized recombinant human TRAIL (rhTRAIL) resistant BT-20 TNBC cells to rhTRAIL induced apoptosis [230]. Quercetin treatment remodels the tumor microenvironment and thus improves the permeation, retention, and antitumor effects of nanoparticles [231]. A nano-carrier-mediated delivery of a combination of topotecan and quercetin facilitated selective uptake of the nanoparticle containing the drug combinations in MDA-MB 231 cells through integrin receptor-mediated endocytosis, followed by intracellular dissociation of the nanoparticle, releasing the drugs which in turn subsequently triggered TNBC cell death [232]. In comparison to drug monotherapy, quercetin co-administration with chemotherapeutic drugs such as cisplatin [233,234,235] and plant-derived compounds (such as resveratrol and curcumin) [236,237] showed improved efficacy in the treatment of different cancers, highlighting the possibility of using quercetin-chemotherapeutic drug/plant derivative combinations in the treatment of TNBCs.


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Jeffrey Dach MD
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