Errors in Oncology-Ignoring the Role of Platelets
Platelets are the little sticky cells in our blood that form clots to stop bleeding. This is a good thing. However, it is not a good thing when platelets are recruited by cancer cells to evade the immune system, induce new blood vessels (angiogenesis) and migrate to distant sites forming metastatic tumor sites.(22-24)(26) Left image Scanning Electron Microscope of Red blood cell (red) surrounded by platelets (yellow) and fibrin forming a clot.Scanning Electron Microscope Image courtesy of science forums.com
Anti-platelet drug, dipyridamole (persantine) is commonly used to inhibit platelet adhesion, for prevention of blood clots after stroke or heart attack, and has a long history of safe use. The main adverse effect of anti-platelet drugs as you might expect is worsening of bleeding.
Over the years, observational studies in patients on the long term anti-platelet drug, dipyridamole, have revealed striking benefits for prevention and treatment of various cancers. This observation led to basic science study of the mechanism of cancer prevention. Clinical trials are underway using Dipyridamole in cancer patients. The results have been amazing.
No Man is an Island
If it is true that “No Man is an Island”, the same can be said about the cancer cell. It cannot exist alone by itself. Cancer cells use the surrounding tissues, called the tumor microenvironment to assist in growth and metastatic spread. (26)
This is where platelets play a role demonstrated on routine blood smears which may reveal “platelet satellitism” in certain hematologic cancers. Left Image, platelet satellitism a common finding on blood smears in cancer patients, the platelets adhere to the outer rim of the cancer cell as in satellites. (4)
Preventing Platelets From Feeding Cancer with Dipyridamole
A 2013 study by Dr Daniella Spano showed that dipyridamole prevents progression of triple negative breast cancer in a mouse xenograft model.(6) Low dose “Dipyridamole significantly reduced primary tumor growth and metastasis” . while high dose “resulted in an almost a total reduction in primary tumors”. (6) “Dipyridamole had significant effects on Wnt, ERK1/2-MAPK and NF-kB pathways in both animal models. Moreover. dipyridamole significantly decreased the infiltration of tumor-associated macrophages and myeloid-derived suppressor cells in primary tumors (p < 0.005), and the inflammatory cytokines.”(6)
Dipyridamole inhibits the phosphodiesterase enzymes that normally break down cAMP, thus increasing cellular cAMP levels. “Dipyridamole inhibits the cellular reuptake of adenosine into platelets, red blood cells and endothelial cells leading to increased extra-cellular concentrations of adenosine.” (8)
Blocking Platelet Derived Growth Factor and Angiogeneisis
Cancer cells use platelet derived growth factor (PDGF) to induce new vessel formation, a process called angiogeneisis. Blocking receptors for PDGF in pericytes results in loss of neovascular growth needed to sustain tumor growth in lymphoma.(28-29) A drug called Gleevec (imatinib) FDA approved for treatment of CLL was found to be a potent blocker of PDGF receptors, and potent angiogenesis inhibitor in a lymphoma xenograft animal model.(28-29)
Histamine as Autocrine Growth Factor
Histamine is an intracellular messenger which promotes platelet aggregation.(13-20) Histamine antagonists have an anti-cancer effect.(16) In an animal model of experimental carcinomas endogenous histamine was critical for cell proliferation. A major effect of histamine is stimulation of cancer cell growth by activating H2 membrane receptors on the cancer cell.(18) Ibrutinib and Cimetidine have potent antihistamine actions, and both have anti-cancer activity. Dipyridamole inhibits COX-2, an inflammatory pathway frequently upregulated in cancer cells.(21)
Conclusion: The commonly used antiplatelet drug, Dipyridamole, is a valuable addition to the treatment and prevention of cancer by virtue of platelet inhibition.
Articles with Related interest
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Fl 33314
Anti-Cancer Effect of Dipyridamole
dipyridamole daily orally (75 mg)
Dipyridamole 75 mg was administered orally three times daily during the FU administration.
Mantle Cell Lymphoma
Am J Clin Pathol. 2001 Apr;115(4):567-70.
Platelet satellitism as presenting finding in mantle cell lymphoma. A case report.
Cesca C1, Ben-Ezra J, Riley RS. Platelet satellitism surrounding polymorphonuclear neutrophils has been observed almost exclusively in EDTA-treated blood at room temperature. The mechanism underlying this phenomenon is not understood fully. We report a case of platelet rosetting around atypical lymphocytes in peripheral blood smears made from EDTA-treated and untreated blood. Flow cytometry of the peripheral blood sample and immunohistochemical stains of the subsequent bone marrow biopsy specimen revealed a monoclonal B-cell population positive for CD5, CD20, and cyclin D1 and negative for CD3 and CD23; cytogenetic findings revealed a complex karyotype that included t(11;14). These findings were consistent with mantle cell lymphoma. To our knowledge, the finding of platelet satellitism involving mantle cell lymphoma cells in peripheral blood has not been reported previously.
5) Rhodes, E. L., et al. “Dipyridamole for treatment of melanoma.” The Lancet 325.8430 (1985): 693.
6) Spano, Daniela, et al. “Dipyridamole prevents triple-negative breast-cancer progression.” Clinical & experimental metastasis 30.1 (2013): 47-68.
Dipyridamole is a widely prescribed drug in ischemic disorders, and it is here investigated for potential clinical use as a new treatment for breast cancer. Xenograft mice bearing triple-negative breast cancer 4T1-Luc or MDA-MB-231T cells were generated. In these in vivo models, dipyridamole effects were investigated for primary tumor growth, metastasis formation, cell cycle, apoptosis, signaling pathways, immune cell infiltration, and serum inflammatory cytokines levels. Dipyridamole significantly reduced primary tumor growth and metastasis formation by intraperitoneal administration. Treatment with 15 mg/kg/day dipyridamole reduced mean primary tumor size by 67.5 % (p = 0.0433), while treatment with 30 mg/kg/day dipyridamole resulted in an almost a total reduction in primary tumors (p = 0.0182).
Experimental metastasis assays show dipyridamole reduces metastasis formation by 47.5 % in the MDA-MB-231T xenograft model (p = 0.0122), and by 50.26 % in the 4T1-Luc xenograft model (p = 0.0292). In vivo dipyridamole decreased activated β-catenin by 38.64 % (p < 0.0001), phospho-ERK1/2 by 25.05 % (p = 0.0129), phospho-p65 by 67.82 % (p < 0.0001) and doubled the expression of IkBα (p = 0.0019), thus revealing significant effects on Wnt, ERK1/2-MAPK and NF-kB pathways in both animal models. Moreover dipyridamole significantly decreased the infiltration of tumor-associated macrophages and myeloid-derived suppressor cells in primary tumors (p < 0.005), and the inflammatory cytokines levels in the sera of the treated mice. We suggest that when used at appropriate doses and with the correct mode of administration, dipyridamole is a promising agent for breast-cancer treatment, thus also implying its potential use in other cancers that show those highly activated pathways.
Wang, Chunmei, et al. “Chemoprevention activity of dipyridamole in the MMTV-PyMT transgenic mouse model of breast cancer.” Cancer Prevention Research 6.5 (2013): 437-447. Cancer Prev Res (Phila).
Dipyridamole (DPM) is widely used to prevent strokes and vascular thrombosis. Combination therapy of DPM and antimetabolites has shown synergistic anticancer activity. This study investigated the chemopreventive effects of DPM in the mouse mammary tumor virus promoter driven polyoma middle T oncoprotein (MMTV-PyMT) metastatic breast cancer model. We also investigated the effects of DPM on gene and miRNA expression. Chemopreventive activity was assessed by comparing the time to onset of palpable lesions, primary tumor growth kinetics and the number of lung metastases in transgenic mice treated with DPM or vehicle. Gene expression and microRNA (miRNA) expression profiles of mammary tumor tissues were then analyzed using the Affymetrix GeneChip® or miRNA 2.0 arrays. Real-time quantitative PCR (qPCR) was used to confirm changes in gene expression. Treatment with DPM beginning at the age of four weeks delayed the onset of palpable lesions, delayed tumor progression and suppressed lung metastasis. Microarray gene expression analysis identified 253 genes differentially expressed between DPM-treated and control mammary tumors. miRNA expression analysis revealed that 53 miRNAs were altered by DPM treatment. The results indicate that DPM has chemoprevention activity against breast cancer tumorigenesis and metastasis in mice. The array analyses provide insights into potential mechanisms of DPM’s chemopreventive effects, involving upregulation of several genes and miRNAs known to suppress cancer growth and/or metastasis and downregulation of genes known to promote cancer. Some of these genes have not been previously studied in breast cancer and may serve as novel molecular targets for breast cancer chemoprevention.
Ge, Shu-Min, et al. “Reverse screening approach to identify potential anti-cancer targets of dipyridamole.” American journal of translational research 8.12 (2016): 5187.
Leblanc, Raphael, and Olivier Peyruchaud. “Metastasis: new functional implications of platelets and megakaryocytes.” Blood 128.1 (2016): 24-31.“It is now well established that platelets are essential for cancer metastasis dissemination and progression to the bone.”
Cancer Metastasis Rev. 2014 Mar; 33(1): 231–269. Platelets and cancer: a casual or causal relationship: revisited David G. Menter, Stephanie C. Tucker, Scott Kopetz, Anil K. Sood, John D. Crissman, and Kenneth V. Honn
Front Oncol. 2014; 4: 245. Involvement of Platelet–Tumor Cell Interaction in Immune Evasion. Potential Role of Podocalyxin-Like Protein 1
Laura Amo,1,† Estíbaliz Tamayo-Orbegozo,1,† Natalia Maruri,1 Cristina Eguizabal,2 Olatz
[CANCER RESEARCH 59, 1295–1300, March 15, 1999]
Lysis of Tumor Cells by Natural Killer Cells in Mice Is Impeded by Platelets1
Bernhard Nieswandt, Michael Hafner, Bernd Echtenacher, and Daniela N. Ma ¨ nnel2
Department of Pathology, Tumor Immunology, University of Regensburg, 93042 Regensburg, Germany
13) Saxena, Satya P., et al. “Histamine is an intracellular messenger mediating platelet aggregation.” Science 243.4898 (1989): 1596-1600.
Inflamm Res. 1998 May;47(5):211-20. The role of histamine in platelet aggregation by physiological and immunological stimuli. Masini E1, Di Bello MG, Raspanti S, Ndisang JF, Baronti R, Cappugi P, Mannaioni PF.
Platelets participate in allergic and inflammatory processes beside their role in haemostasis and thrombosis. This paper reports the level, the uptake, the metabolism and the release of histamine in human platelets. The effects of exogenous histamine, as well as the receptor and signal transduction of these effects, are also described.
METHODS: Purified suspensions of platelets, prepared from healthy volunteers and from atopic patients, were exposed in vitro to physiological and immunological stimuli. Platelet aggregation was measured by the increase in light transmission; histamine content and release, as well as cytosolic free Ca2+ concentration, were measured fluorimetrically. Platelet histamine forming capacity, and the uptake of exogenous histamine, were measured with a radioisotopic method.
RESULTS: Human platelets contain 72.5 +/- 9.6pmoles of histamine x 10(9) platelets, and their capacity to form histamine is 18.7 +/- 3.5pmoles h(-1)g(-1) protein, which is reduced by alpha-fluoromethylhistidine (10(-5) M) a selective inhibitor of the specific histidine decarboxylase. Human platelets take up the preformed amine by a calcium and energy-dependent process, and the uptake of histamine is reduced by mepyramine, an H1-receptor antagonist, and N,N-diethyl-2-[4-(
CONCLUSIONS:The synergistic effect between histamine and other monoamines on platelet aggregation may explain some aspects of allergic vasculitis in which platelet aggregation is present.
Histamine and platelets
Science. 1989 Mar 24;243(4898):1596-9. Histamine is an intracellular messenger mediating platelet aggregation. Saxena SP1, Brandes LJ, Becker AB, Simons KJ, LaBella FS, Gerrard JM. Author information Department of Pediatrics, University of Manitoba, Winnipeg, Canada.
Inhibition of human platelet aggregation by N,N-diethyl-2-[4-(
Inflamm Allergy Drug Targets. 2010 Jul;9(3):146-57. Histamine and histamine receptor antagonists in cancer biology. Blaya B1, Nicolau-Galmés F, Jangi SM, Ortega-Martínez I, Alonso-Tejerina E, Burgos-Bretones J, Pérez-Yarza G, Asumendi A, Boyano MD.
Histamine has been demonstrated to be involved in cell proliferation, embryonic development, and tumour growth. These various biological effects are mediated through the activation of specific histamine receptors (H1, H2, H3, and H4) that differ in their tissue expression patterns and functions. Although many in vitro and in vivo studies of the modulatory roles of histamine in tumour development and metastasis have been reported, the effect of histamine in the progression of some types of tumours remains controversial; however, recent findings on the role of histamine in the immune system have shed new light on this question. This review focuses on the recent advances in understanding the roles of histamine and its receptors in tumour biology. We report our recent observations of the anti-tumoural effect of H1 histamine antagonists on experimental and human melanomas. We have found that in spite of exogenous histamine stimulated human melanoma cell proliferation, clonogenic ability and migration activity in a dose-dependent manner, the melanoma tumour growth was not modulated by in vivo histamine treatment. On the contrary, terfenadine-treatment in vitro induced melanoma cell death by apoptosis and in vivo terfenadine treatment significantly inhibited tumour growth in murine models. These observations increase our understanding of cancer biology and may inspire novel anticancer therapeutic strategies.
Semin Cancer Biol. 2000 Feb;10(1):15-23. Histamine as an autocrine growth factor: an unusual role for a widespread mediator. Rivera ES1, Cricco GP, Engel NI, Fitzsimons CP, Martín GA, Bergoc RM.
The involvement of histamine in cancer growth represents an old controversy and direct experimental evidence proving this hypothesis is not still available. In this paper we review the most relevant mechanisms referring to the role of histamine receptors, histidine decarboxylase and histamine release in the onset of an autocrine loop, that enables histamine to act as an autocrine growth factor. We postulate that this autocrine loop, that has been studied in an experimental mammary carcinoma model induced in rats, may be present in different human neoplasias. Therefore, the better understanding of this novel regulatory pathway that is controlled by histamine may contribute to identifying new therapeutic targets.
Agents Actions. 1994 Nov;43(1-2):17-20.
Histamine as an autocrine growth factor in experimental mammary carcinomas.
Cricco GP1, Davio CA, Martin G, Engel N, Fitzsimons CP, Bergoc RM, Rivera ES.
In order to determine the role of endogenous histamine in the regulation of cell growth, the in vitro action of fluoromethyl-histidine (MFMH) was studied in experimental mammary carcinomas induced in rats. Tumor cells were cultured in soft agar using the clonogenic agar technique. The MFMH was added in different concentrations (0.01-100 microM). The effect observed was a 60% inhibition on colony formation with a maximal effect at concentrations over 10 microM. This action was completely reverted by the H2 agonists dimaprit and arpromidine with an IC50 value of 1 microM. The action of the H2 agonists when added alone was a significant increase in cell proliferation (135%), while the H1 agonist produced a dose-dependent inhibition on cell growth. In these experimental carcinomas endogenous histamine is critical for cell proliferation and one of its major effects may be the stimulation of cell growth by acting on specific H2 membrane receptors.
Biochem Pharmacol. 1995 Jun 29;50(1):91-6.
H1 and H2 histamine receptors in N-nitroso-N-methylurea (NMU)-induced carcinomas with atypical coupling to signal transducers. Davio CA1, Cricco GP, Bergoc RM, Rivera ES.
Two specific binding sites for histamine were characterized in the cell membrane of N-nitroso-N-methylurea (NMU)-induced tumors. The first one, with higher affinity (Kd = 4 +/- 2 nM), was further identified as an H2 type, while the lower affinity one (35 +/- 10 nM) corresponded to an H1 receptor. Histamine concentrations up to 50 nM, as well as H2 agonists, significantly enhanced the phosphoinositide turnover by acting through higher affinity H2 receptors. On the other hand, histamine at concentrations over 50 nM and H1 agonists produced a 100% increase in cAMP levels in a response specifically blocked by mepyramine. These H1 and H2 histamine receptors that exhibit different linkages to second messenger systems may prove to be a characteristic of cells with a high proliferating capacity, such as undifferentiated or transformed cells.
Br J Pharmacol. 2010 Oct; 161(4): 755–767.
Histamine receptors and cancer pharmacology
Vanina A Medina1,2 and Elena S Rivera1
Dipyridimole and COX-2 Inhibition
21) Eur J Pharmacol. 2011 Jan 10;650(1):445-50. Dipyridamole inhibits lipopolysaccharide-induced cyclooxygenase-2 and monocyte chemoattractant protein-1 via heme oxygenase-1-mediated reactive oxygen species reduction in rat mesangial cells.
Chen YC1, Chen CH, Ko WS, Cheng CY, Sue YM, Chen TH.
Dipyridamole contributes to its beneficial effects on inflammatory responses in many cell types. The anti-inflammatory mechanisms of dipyridamole on glomerular mesangial cells are mostly uncharacterized. In this study, we monitored the influence of dipyridamole on the expression levels of cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein-1 (MCP-1) in rat mesangial cells stimulated with lipopolysaccharide. Dipyridamole was found to inhibit lipopolysaccharide-induced COX-2 and MCP-1 expression, and reduced lipopolysaccharide-induced reactive oxygen species generation in rat mesangial cells. This inhibitory effect of dipyridamole is independent on cyclic AMP and cyclic GMP increase. Tin protoporphyrin IX (SnPP), a heme oxygenase-1(HO-1) inhibitor, blocked the inhibitory effect of dipyridamole on lipopolysaccharide-induced COX-2 and MCP-1 expression. By applying specific inhibitors in rat mesangial cells, ERK1/2 and p38 MAPK signaling pathways were demonstrated to be involved in the lipopolysaccharide-induced inflammatory responses, and were inhibited by SnPP and N-acetylcysteine treatment. Additionally, dipyridamole was also found to upregulate HO-1 in rat mesangial cells. Therefore, our data suggest that dipyridamole inhibits the expression of COX-2 and MCP-1 in lipopolysaccharide-treated rat mesangial cells via HO-1-mediated reactive oxygen species reduction.
Platelet Activation impairs Killer T Cell Function
22) Blood. 2005 Jan 1;105(1):178-85. Epub 2004 Sep 14.
Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells.
Palumbo JS1, Talmage KE, Massari JV, La Jeunesse CM, Flick MJ, Kombrinck KW, Jirousková M, Degen JL.
To test the hypothesis that platelet activation contributes to tumor dissemination, we studied metastasis in mice lacking Galphaq, a G protein critical for platelet activation. Loss of platelet activation resulted in a profound diminution in both experimental and spontaneous metastases. Analyses of the distribution of radiolabeled tumor cells demonstrated that platelet function, like fibrinogen, significantly improved the survival of circulating tumor cells in the pulmonary vasculature. More detailed studies showed that the increase in metastatic success conferred by either platelets or fibrinogen was linked to natural killer cell function. Specifically, the pronounced reduction in tumor cell survival observed in fibrinogen- and Galphaq-deficient mice relative to control animals was eliminated by the immunologic or genetic depletion of natural killer cells. These studies establish an important link between hemostatic factors and innate immunity and indicate that one mechanism by which the platelet-fibrin(ogen) axis contributes to metastatic potential is by impeding natural killer cell elimination of tumor cells.
23) Elaskalani, Omar, et al. “Targeting Platelets for the Treatment of Cancer.” Cancers 9.7 (2017): 94. The majority of cancer-associated mortality results from the ability of tumour cells to metastasise leading to multifunctional organ failure and death. Disseminated tumour cells in the blood circulation are faced with major challenges such as rheological shear stresses and cell-mediated cytotoxicity mediated by natural killer cells. Nevertheless, circulating tumour cells with metastatic ability appear equipped to exploit host cells to aid their survival. Despite the long interest in targeting tumour-associated host cells such as platelets for cancer treatment, the clinical benefit of this strategy is still under question. In this review, we provide a summary of the latest mechanistic and clinical evidence to evaluate the validity of targeting platelets in cancer.
within the blood circulation, platelet-cloaked tumour cells can bypass natural killer
cancer cell adhesion to platelets is vital for successful metastasis, which can be mediated through surface proteins and predispose platelet activation
Blockage of Platelet Derived Growth Factor – resulted in rapid sustained complete remission
treatment of the transgenic mice with imatinib – GLEEVEC
24) Nat Med. 2012 Nov;18(11):1699-704. doi: 10.1038/nm.2966. Epub 2012 Oct 14.
PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas.
Laimer D1, Dolznig H, Kollmann K, Vesely PW, Schlederer M, Merkel O, Schiefer AI, Hassler
Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin’s lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK-triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-β (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-ALK(+) ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.
25) Ruan, Jia, et al. “Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes.” Blood 121.26 (2013): 5192-5202.
26) Yan, MengJie, and Paul Jurasz. “The role of platelets in the tumor microenvironment: From solid tumors to leukemia.” Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1863.3 (2016): 392-400.
27) From the Townsend Letter for Doctors & Patients Letter to the Editor Further Strategies in Treating Advanced Cancer July 2003
cimetidine inhibits T-suppressor cells and helps to liberate our cancer-killing lymphocytes.
cimetidine, 1,000mg a day.
dipyridamole at 300mg a day
Digitalis 0.125 a day
imatinib Gleevec- blocks platelet derived growth factor
28) Ruan, Jia, et al. “Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes.” Blood 121.26 (2013): 5192-5202.
Pericytes and vascular smooth muscle cells (VSMCs), which are recruited to developing blood vessels by platelet-derived growth factor BB, support endothelial cell survival and vascular stability. Here, we report that imatinib, a tyrosine kinase inhibitor of platelet-derived growth factor receptor β (PDGFRβ), impaired growth of lymphoma in both human xenograft and murine allograft models.
Lymphoma cells themselves neither expressed PDGFRβ nor were growth inhibited by imatinib. Tumor growth inhibition was associated with decreased microvascular density and increased vascular leakage. In vivo, imatinib induced apoptosis of tumor-associated PDGFRβ+ pericytes and loss of perivascular integrity. In vitro, imatinib inhibited PDGFRβ+ VSMC proliferation and PDGF-BB signaling, whereas small interfering RNA knockdown of PDGFRβ in pericytes protected them against imatinib-mediated growth inhibition. Fluorescence-activated cell sorter analysis of tumor tissue revealed depletion of pericytes, endothelial cells, and their progenitors following imatinib treatment. Compared with imatinib, treatment with an anti-PDGFRβ monoclonal antibody partially inhibited lymphoma growth. Last, microarray analysis (Gene Expression Omnibus database accession number GSE30752) of PDGFRβ+ VSMCs following imatinib treatment showed down-regulation of genes implicated in vascular cell proliferation, survival, and assembly, including those representing multiple pathways downstream of PDGFRβ. Taken together, these data indicate that PDGFRβ+ pericytes may represent a novel, nonendothelial, antiangiogenic target for lymphoma therapy.
29) Chute, John P., and Heather A. Himburg. “Imatinib tackles lymphoma via the PDGFRβ+ pericyte.” Blood 121.26 (2013): 5107-5108.