Dipyridamole intervention of breast cell carcinogenesis

Abstract

Dietary prevention is a cost-efficient strategy to reduce the risk of human cancers. More than 85% breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens through a multistep and multiyear disease process. We used our chronically induced cellular carcinogenesis model as a target to search for preventive agents capable of blocking breast cell carcinogenesis. Dipyridamole (DPM), at a non-cytotoxic physiologically achievable dose of 10 nmol/L, effectively blocked breast cell carcinogenesis induced by cumulative exposures to three unrelated carcinogens 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), benzo[a]pyrene (B[a]P), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The ability of DPM to block H-Ras upregulation, thus blocking ERK pathway activation, reactive oxygen species (ROS) elevation, and DNA damage in each exposure, may account for its mechanisms in intervention of carcinogenesis induced by cumulative exposures to PhIP. Likewise, DPM's ability to block ROS elevation and DNA damage may account for its mechanisms in intervention of carcinogenesis chronically induced by NNK and B[a]P, as well. DPM is approved by the Food and Drug Administration to control platelet aggregation and vasoconstriction in patients. Our study revealed, for the first time, the novel ability of DPM to block breast cell carcinogenesis induced by three unrelated carcinogens. DPM should be seriously considered as a chemopreventive agent in development of strategies for reducing the risk of sporadic breast cancer associated with long-term exposure to environmental carcinogens.

Evaluation of the anticancer activity of dipyridamole and Imatinib mesylate compounds against breast cancer cell line and related biochemical and genetic changes

“…Another study showed mild down-regulation of Bcl2 and extremely significant up regular of Bax in solid Ehrlich carcinoma-bearing mice. In our studies, dipyridamole made overexpression for CYC gene in 231 cell line as in anther studies dipyridamole increased intracellular c-AMP and inhibited Erk1/2 activation in of human peritoneal mesothelial cell proliferation (Padala et al, 2017;Choudhary et al, 2014). Some studies suggested that DIM possesses beneficial properties, either direct or indirect effects, such as downstream effects on cell signalling proliferation inhibition, anti-inflammatory and antioxidant properties (Sureechatchaiyan et al, 2018).…”

Inhibition of breast cancer cell migration by activation of cAMP signaling

“…These observations, as well as our finding in this study that PDE8A is prominently expressed at the mRNA level in all breast cancer cells and tissues examined, and the recent finding that PDE8A binds to and regulates raf-1 [31], which controls many fundamental biological processes, suggests that PDE8A may provide an excellent novel target for inhibiting breast cancer metastasis. Of note, the nonselective PDE inhibitor, dipyridamole, which in contrast to the nonselective methylxanthine PDE inhibitors, is capable of inhibiting PDE8A, and which we show to significantly inhibit breast cancer cell migration, was recently shown to inhibit breast cancer tumorigenesis and metastasis in animal models [59][60][61], further suggesting that PDE8A may represent an excellent new target for breast cancer treatment.…”

Use of dipyridamole is associated with lower risk of lymphoid neoplasms: a propensity score‐matched cohort study

“…Emerging evidence, in vitro and in vivo, has shown an anti-cancer effect of dipyridamole via its anti-viral activity, immunoregulation, autophagic flux blockade, anti-proliferative activity, inhibiting tumour cell metastasis, and its enhancing the cytotoxicity of anti-cancer drugs. [8][9][10][11][12][13][14][15][16] The anti-cancer effects of dipyridamole are mainly involved in PDE inhibitions, including PDE10, PDE8, PDE5, and PDE4. 1,2 Growing evidence suggests that PDEs play an important role in carcinogenesis via influencing the level of cAMP and/or cGMP; thus, PDEs have the potential to be a novel target for inhibiting tumour cell growth.…”

“…[5][6][7] Recently, a growing amount of evidence from preclinical research indicated the anti-cancer activity of dipyridamole on several types of malignancies, including colorectal, breast, prostate, or haematological malignancies. [8][9][10][11][12][13][14][15][16] Dipyridamole was recently found to prevent Epstein-Barr virus (EBV) re-activation, indicating a possibility to be repurposed as a nontoxic anti-viral drug to prevent EBV-related diseases. 10 It is known that EBV was originally discovered in cells from Burkitt's lymphoma, and the re-activation has been demonstrated to directly and indirectly associate with lymphomagenesis.…”