Dipyridamole enhances the anti-cancer ability of aspirin against colorectal cancer by inducing apoptosis in an unfolded protein response-dependent manner
Tóm tắt
Available evidence indicates that dipyridamole enhances the anti-thrombotic effects of aspirin for the prevention of secondary strokes. Aspirin is a well-known non-steroid anti-inflammatory drug. This anti-inflammatory property has turned aspirin into a potential drug for inflammation-related cancers such as colorectal cancer (CRC). Here, we aimed to explore whether the anti-cancer effect of aspirin against CRC could be improved by combined administration with dipyridamole. Population-based clinical data analysis was conducted to assess a possible therapeutic effect of combined dipyridamole and aspirin treatment in inhibiting CRC compared with either monotherapy. This therapeutic effect was further verified in different CRC mouse models, i.e. an orthotopic xenograft mouse model, an AOM/DSS mouse model, an Apcmin/+ mouse model and a patient derived xenograft (PDX) mouse model. The in vitro effects of the drugs on CRC cells were tested using CCK8 and flow cytometry assays. RNA-Seq, Western blotting, qRT-PCR and flow cytometry were used to identify the underlying molecular mechanisms. We found that dipyridamole combined with aspirin had a better inhibitory effect on CRC than either monotherapy alone. The enhanced anti-cancer effect of the combined use of dipyridamole with aspirin was found to rely on the induction of an overwhelmed endoplasmic reticulum (ER) stress and subsequent pro-apoptotic unfolded protein response (UPR), which was different from the anti-platelet effect. Our data indicate that the anti-cancer effect of aspirin against CRC may be enhanced by combined administration with dipyridamole. In case further clinical studies confirm our findings, these may be repurposed as adjuvant agents.
Tài liệu tham khảo
F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018)
J.H. Kim, Chemotherapy for colorectal cancer in the elderly. World J. Gastroenterol. 21, 5158–5166 (2015)
P. Balakumar, Y.H. Nyo, R. Renushia, D. Raaginey, A.N. Oh, R. Varatharajan, S.A. Dhanaraj, Classical and pleiotropic actions of dipyridamole: Not enough light to illuminate the dark tunnel? Pharmacol. Res. 87, 144–50 (2014)
M. Keller, K. Rohlf, A. Glotzbach, G. Leonhardt, S. Luke, K. Derksen, O. Demirci, D. Gocener, M. AlWahsh, J. Lambert, C. Lindskog, M. Schmidt, W. Brenner, M. Baumann, E. Zent, M.L. Zischinsky, B. Hellwig, K. Madjar, J. Rahnenfuhrer, N. Overbeck, J. Reinders, C. Cadenas, J.G. Hengstler, K. Edlund, R. Marchan, Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2 + breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth. J. Exp. Clin. Cancer Res. 42, 25 (2023)
J. Gao, C. Zhou, Y. Zhong, L. Shi, X. Luo, H. Su, M. Li, Y. Xu, N. Zhang, H. Zhou, Dipyridamole interacts with the N-terminal domain of HSP90 and antagonizes the function of the chaperone in multiple cancer cell lines. Biochem. Pharmacol. 207, 115376 (2023)
S.M. Ge, D.L. Zhan, S.H. Zhang, L.Q. Song, W.W. Han, Reverse screening approach to identify potential anti-cancer targets of dipyridamole. Am. J. Transl Res. 8, 5187–5198 (2016)
M.P. Thome, C. Borde, A.K. Larsen, J.A.P. Henriques, G. Lenz, A.E. Escargueil, V. Marechal, Dipyridamole as a new drug to prevent Epstein-Barr virus reactivation. Antiviral Res. 172, 104615 (2019)
D. Spano, J.C. Marshall, N. Marino, D. De Martino, A. Romano, M.N. Scoppettuolo, A.M. Bello, V. Di Dato, L. Navas, G. De Vita, C. Medaglia, P.S. Steeg, M. Zollo, Dipyridamole prevents triple-negative breast-cancer progression. Clin. Exp. Metastasis 30, 47–68 (2013)
M.P. Thome, L.C. Pereira, G.R. Onzi, F. Rohden, M. Ilha, F.T. Guma, M.R. Wink, G. Lenz, Dipyridamole impairs autophagic flux and exerts antiproliferative activity on prostate cancer cells. Exp. Cell. Res. 382, 111456 (2019)
S. Zhou, H. Xu, Q. Tang, H. Xia, F. Bi, Dipyridamole enhances the cytotoxicities of trametinib against Colon cancer cells through combined targeting of HMGCS1 and MEK Pathway. Mol. Cancer Ther. 19, 135–146 (2020)
S. Choudhary, S. Sood, H.C. Wang, Dipyridamole intervention of breast cell carcinogenesis. Mol. Carcinog. 53, 243–252 (2014)
G.N. Tzanakakis, K.C. Agarwal, M.P. Vezeridis, Prevention of human pancreatic cancer cell-induced hepatic metastasis in nude mice by dipyridamole and its analog RA-233. Cancer 71, 2466–2471 (1993)
R.R. Mishra, N. Belder, S.A. Ansari, M. Kayhan, H. Bal, U. Raza, P.G. Ersan, U.M. Tokat, E. Eyupoglu, O. Saatci, P. Jandaghi, S. Wiemann, A. Uner, C. Cekic, Y. Riazalhosseini, O. Sahin, Reactivation of cAMP pathway by PDE4D Inhibition Represents a Novel Druggable Axis for overcoming tamoxifen resistance in ER-positive breast Cancer. Clin. Cancer Res. 24, 1987–2001 (2018)
J. Longo, P.J. Mullen, R. Yu, J.E. van Leeuwen, M. Masoomian, D.T.S. Woon, Y. Wang, E.X. Chen, R.J. Hamilton, J.M. Sweet, T.H. van der Kwast, N.E. Fleshner, L.Z. Penn, An actionable sterol-regulated feedback loop modulates statin sensitivity in prostate cancer. Mol. Metab. 25, 119–130 (2019)
A. Mehta, B.M. Patel, Therapeutic opportunities in colon cancer: focus on phosphodiesterase inhibitors. Life Sci. 230, 150–161 (2019)
W. Huang, J. Sundquist, K. Sundquist, J. Ji, Phosphodiesterase-5 inhibitors use and risk for mortality and metastases among male patients with colorectal cancer. Nat. Commun. 11, 3191 (2020)
W. Huang, J. Sundquist, K. Sundquist, J. Ji, Use of Phosphodiesterase 5 Inhibitors Is Associated With Lower Risk of Colorectal Cancer in Men With Benign Colorectal Neoplasms. Gastroenterology 157, 672–681 e4 (2019)
K. Krishnan, Z.K. Law, J.S. Minhas, P.M. Bath, T.G. Robinson, N. Sprigg, A. Mavilakandy, T.J. England, D. Eveson, A. Mistri, J. Dawson, J.P. Appleton, Antiplatelet treatment for acute secondary prevention of non-cardioembolic minor stroke / transient ischaemic attack: an update for the acute physician. Clin. Med. (Lond) 22, 449–454 (2022)
X. Hou, K. Cen, Y. Cui, Y. Zhang, X. Feng, Antiplatelet therapy for secondary prevention of lacunar stroke: a systematic review and network meta-analysis. Eur. J. Clin. Pharmacol. 79, 63–70 (2023)
J. Hybiak, I. Broniarek, G. Kiryczynski, L.D. Los, J. Rosik, F. Machaj, H. Slawinski, K. Jankowska, E. Urasinska, Aspirin and its pleiotropic application. Eur. J. Pharmacol. 866, 172762 (2020)
A. Greco, S. Finocchiaro, D.J. Angiolillo, D. Capodanno, Advances in the Available Pharmacotherapy for the Management of Acute Coronary Syndromes in Patients Presenting Without Persistent ST-segment Elevation (Expert Opin Pharmacother, 2023)
H. Hua, H. Zhang, Q. Kong, J. Wang, Y. Jiang, Complex roles of the old drug aspirin in cancer chemoprevention and therapy. Med. Res. Rev. 39, 114–145 (2019)
A. Grancher, P. Michel, F. Di Fiore, D. Sefrioui, Colorectal cancer chemoprevention: is aspirin still in the game? Cancer Biol. Ther. 23, 446–461 (2022)
J. Ji, J. Sundquist, K. Sundquist, Use of terbinafine and risk of death in patients with prostate cancer: a population-based cohort study. Int. J. Cancer 144, 1888–1895 (2019)
T.G. Simon, A.S. Duberg, S. Aleman, R.T. Chung, A.T. Chan, J.F. Ludvigsson, Association of aspirin with Hepatocellular Carcinoma and Liver-Related mortality. N Engl. J. Med. 382, 1018–1028 (2020)
M.E. Charlson, P. Pompei, K.L. Ales, C.R. MacKenzie, A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J. Chronic Dis. 40, 373–383 (1987)
X.L. Zhang, L.P. Hu, Q. Yang, W.T. Qin, X. Wang, C.J. Xu, G.A. Tian, X.M. Yang, L.L. Yao, L. Zhu, H.Z. Nie, Q. Li, Q. Xu, Z.G. Zhang, Y.L. Zhang, J. Li, Y.H. Wang, S.H. Jiang, CTHRC1 promotes liver metastasis by reshaping infiltrated macrophages through physical interactions with TGF-beta receptors in colorectal cancer. Oncogene 40, 3959–3973 (2021)
T. Shimura, S. Toden, N.L. Komarova, C. Boland, D. Wodarz, A. Goel, A comprehensive in vivo and mathematic modeling-based kinetic characterization for aspirin-induced chemoprevention in colorectal cancer. Carcinogenesis 41, 751–760 (2020)
R. Zhao, O.O. Coker, J. Wu, Y. Zhou, L. Zhao, G. Nakatsu, X. Bian, H. Wei, A.W.H. Chan, J.J.Y. Sung, F.K.L. Chan, E. El-Omar, J. Yu, Aspirin Reduces Colorectal Tumor Development in Mice and Gut Microbes Reduce its Bioavailability and Chemopreventive Effects. Gastroenterology 159, 969–983 e4 (2020)
T.C. Chou, P. Talalay, Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 22, 27–55 (1984)
W. Huang da, B.T. Sherman, R.A. Lempicki, Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37, 1–13 (2009)
W. Huang da, B.T. Sherman, R.A. Lempicki, Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009)
A. Subramanian, P. Tamayo, V.K. Mootha, S. Mukherjee, B.L. Ebert, M.A. Gillette, A. Paulovich, S.L. Pomeroy, T.R. Golub, E.S. Lander, J.P. Mesirov, Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. U S A 102, 15545–15550 (2005)
V.K. Mootha, C.M. Lindgren, K.F. Eriksson, A. Subramanian, S. Sihag, J. Lehar, P. Puigserver, E. Carlsson, M. Ridderstrale, E. Laurila, N. Houstis, M.J. Daly, N. Patterson, J.P. Mesirov, T.R. Golub, P. Tamayo, B. Spiegelman, E.S. Lander, J.N. Hirschhorn, D. Altshuler, L.C. Groop, PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003)
Y.X. Feng, E.S. Sokol, C.A. Del Vecchio, S. Sanduja, J.H. Claessen, T.A. Proia, D.X. Jin, F. Reinhardt, H.L. Ploegh, Q. Wang, P.B. Gupta, Epithelial-to-mesenchymal transition activates PERK-eIF2alpha and sensitizes cells to endoplasmic reticulum stress. Cancer Discov 4, 702–715 (2014)
S.T. Nawrocki, J.S. Carew, K. Dunner Jr., L.H. Boise, P.J. Chiao, P. Huang, J.L. Abbruzzese, D.J. McConkey, Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res. 65, 11510–11519 (2005)
J. Berg, H. Fellier, T. Christoph, J. Grarup, D. Stimmeder, The analgesic NSAID lornoxicam inhibits cyclooxygenase (COX)-1/-2, inducible nitric oxide synthase (iNOS), and the formation of interleukin (IL)-6 in vitro. Inflamm. Res. 48, 369–379 (1999)
T.T. Ashburn, K.B. Thor, Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov 3, 673–683 (2004)
P. Gresele, S. Momi, M. Malvestiti, M. Sebastiano, Platelet-targeted pharmacologic treatments as anti-cancer therapy. Cancer Metastasis Rev 36, 331–355 (2017)
M. Massaro, E. Scoditti, M.A. Carluccio, M. Pellegrino, N. Calabriso, C. Storelli, G. Martines, R. De Caterina, Dipyridamole decreases inflammatory metalloproteinase-9 expression and release by human monocytes. Thromb. Haemost 109, 280–289 (2013)
A.S. Weyrich, M.M. Denis, J.R. Kuhlmann-Eyre, E.D. Spencer, D.A. Dixon, G.K. Marathe, T.M. McIntyre, G.A. Zimmerman, S.M. Prescott, Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates. Circulation 111, 633–642 (2005)
M. Ciacciarelli, C. Zerbinati, F. Violi, L. Iuliano, Dipyridamole: a drug with unrecognized antioxidant activity. Curr. Top. Med. Chem. 15, 822–829 (2015)
S. Chakrabarti, P. Blair, C. Wu, J.E. Freedman, Redox state of dipyridamole is a critical determinant for its beneficial antioxidant and antiinflammatory effects. J. Cardiovasc. Pharmacol. 50, 449–457 (2007)
N. Suzuki, S. Sekiya, I. Sugano, T. Kojima, H. Yamamori, Y. Takakubo, Dipyridamole combined with tumor necrosis factor-alpha enhances inhibition of proliferation in human tumor cell lines. Jpn J. Cancer Res. 86, 761–769 (1995)
N. Suzuki, Y. Oiwa, I. Sugano, N. Inaba, S. Sekiya, I. Fukazawa, J. Yoshida, Y. Takakubo, E. Isogai, M. Saito-Ebihara, Dipyridamole enhances an anti-proliferative effect of interferon in various types of human tumor cells. Int. J. Cancer 51, 627–633 (1992)
D.A. Drew, Y. Cao, A.T. Chan, Aspirin and colorectal cancer: the promise of precision chemoprevention. Nat. Rev. Cancer 16, 173–186 (2016)
S.A. Oakes, Endoplasmic reticulum stress signaling in Cancer cells. Am. J. Pathol. 190, 934–946 (2020)
S. Bartoszewska, J.F. Collawn, Unfolded protein response (UPR) integrated signaling networks determine cell fate during hypoxia. Cell. Mol. Biol. Lett. 25, 18 (2020)
H. Niu, Y. Zhang, F. Zhao, S. Mo, W. Cao, Y. Ye, Y. Zhao, Reductive stress imaging in the endoplasmic reticulum by using living cells and zebrafish. Chem. Commun. (Camb) 55, 9629–9632 (2019)
J.D. Malhotra, R.J. Kaufman, Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid. Redox Signal. 9, 2277–2293 (2007)
P.I. Merksamer, A. Trusina, F.R. Papa, Real-time redox measurements during endoplasmic reticulum stress reveal interlinked protein folding functions. Cell 135, 933–947 (2008)
C. Hetz, K. Zhang, R.J. Kaufman, Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell. Biol. 21, 421–438 (2020)
H. Urra, E. Dufey, T. Avril, E. Chevet, C. Hetz, Endoplasmic reticulum stress and the Hallmarks of Cancer. Trends Cancer 2, 252–262 (2016)