Generic placeholder image

Recent Patents on Anti-Cancer Drug Discovery

Editor-in-Chief

ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Research Article

Siah2 Inhibitor and the Metabolic Antagonist Oxamate Retard Colon Cancer Progression and Downregulate PD1 Expression

Author(s): Sherin Zakaria, Samar Elsebaey*, Shady Allam, Walied Abdo and Alaa El-Sisi

Volume 19, Issue 1, 2024

Published on: 08 February, 2023

Page: [80 - 92] Pages: 13

DOI: 10.2174/1574892818666230116142606

Price: $65

conference banner
Abstract

Background: Solid tumors such as colon cancer are characterized by rapid and sustained cell proliferation, which ultimately results in hypoxia, induction of hypoxia-inducible factor- 1α (HIF-1α), and activation of glycolysis to promote tumor survival and immune evasion. We hypothesized that a combinatorial approach of menadione (MEN) as an indirect HIF-1α inhibitor and sodium oxamate (OX) as a glycolysis inhibitor may be a promising treatment strategy for colon cancer.

Objectives: We investigated the potential efficacy of this combination for promoting an antitumor immune response and suppressing tumor growth in a rat model of colon cancer.

Methods: Colon cancer was induced by once-weekly subcutaneous injection of 20 mg/kg dimethylhydrazine (DMH) for 16 weeks. Control rats received the vehicle and then no further treatment (negative control) or MEN plus OX for 4 weeks (drug control). Dimethylhydrazine-treated rats were then randomly allocated to four groups: DMH alone group and other groups treated with MEN, OX, and a combination of (MEN and OX) for 4 weeks. Serum samples were assayed for the tumor marker carbohydrate antigen (CA19.9), while expression levels of HIF-1α, caspase-3, PHD3, LDH, and PD1 were evaluated in colon tissue samples by immunoassay and qRT-PCR. Additionally, Ki-67 and Siah2 expression levels were examined by immunohistochemistry.

Results: The combination of MEN plus OX demonstrated a greater inhibitory effect on the expression levels of HIF-1α, Siah2, LDH, Ki-67, and PD1, and greater enhancement of caspase-3 and PHD3 expression in colon cancer tissues than either drug alone.

Conclusion: Simultaneous targeting of hypoxia and glycolysis pathways by a combination of MEN and OX could be a promising therapy for inhibiting colon cancer cell growth and promoting antitumor immunity. Few recent patents are also reviewed in this article.

Keywords: Colon cancer, menadione, hypoxia, glycolysis, oxamate, PD1.

« Previous
[1]
Lampidis TJ, Priebe W. Cancer treatment including glycolytic inhibitors Patent No. US7160865B2, 2007.
[2]
Yamagishi H, Kuroda H, Imai Y, Hiraishi H. Molecular pathogenesis of sporadic colorectal cancers. Chin J Cancer 2016; 35: 1-8.
[http://dx.doi.org/10.1186/s40880-015-0066-y] [PMID: 26738600]
[3]
Rosenberg DW, Giardina C, Tanaka T. Mouse models for the study of colon carcinogenesis. Carcinogenesis 2008; 30(2): 183-96.
[http://dx.doi.org/10.1093/carcin/bgn267] [PMID: 19037092]
[4]
Perše M, Cerar A. Morphological and molecular alterations in 1,2 dimethylhydrazine and azoxymethane induced colon carcinogenesis in Rats. J Biom Biotec 2011; 2011: 473964.
[http://dx.doi.org/10.1155/2011/473964] [PMID: 21253581]
[5]
Yu S, Zhou R, Yang T, et al. Hypoxia promotes colorectal cancer cell migration and invasion in a SIRT1-dependent manner. Cancer Cell Int 2019; 19: 116.
[http://dx.doi.org/10.1186/s12935-019-0819-9] [PMID: 31068761]
[6]
Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell 2012; 148(3): 399-408.
[http://dx.doi.org/10.1016/j.cell.2012.01.021] [PMID: 22304911]
[7]
Chung DC, Mizukami Y. Combination therapy for preventing angiogenesis Patent No.US20080306002A1, 2008.
[8]
Semenza GL. Targeting hypoxia-inducible factor 1 to stimulate tissue vascularization. J Investig Med 2016; 64(2): 361-3.
[http://dx.doi.org/10.1097/JIM.0000000000000206] [PMID: 25955799]
[9]
Lipkowitz S, Weissman AM. RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis. Nat Rev Cancer 2011; 11(9): 629-43.
[http://dx.doi.org/10.1038/nrc3120] [PMID: 21863050]
[10]
Sormendi S, Wielockx B. Hypoxia pathway proteins as central mediators of metabolism in the tumor cells and their microenvironment. Front Immunol 2018; 9: 40.
[http://dx.doi.org/10.3389/fimmu.2018.00040]
[11]
Adam MG, Matt S, Christian S, et al. SIAH ubiquitin ligases regulate breast cancer cell migration and invasion independent of the oxygen status. Cell Cycle 2015; 14(23): 3734-47.
[http://dx.doi.org/10.1080/15384101.2015.1104441] [PMID: 26654769]
[12]
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009; 324(5930): 1029-33.
[http://dx.doi.org/10.1126/science.1160809] [PMID: 19460998]
[13]
Zhao Y, Butler EB, Tan M. Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis 2013; 4(3): e532.
[http://dx.doi.org/10.1038/cddis.2013.60] [PMID: 23470539]
[14]
Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol 1927; 8(6): 519-30.
[http://dx.doi.org/10.1085/jgp.8.6.519] [PMID: 19872213]
[15]
Sonveaux P, Végran F, Schroeder T, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 2008; 118(12): 3930-42.
[http://dx.doi.org/10.1172/JCI36843] [PMID: 19033663]
[16]
Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM, Karagiannis TC. Cancer metabolism and the Warburg effect: The role of HIF-1 and PI3K. Mol Biol Rep 2015; 42(4): 841-51.
[http://dx.doi.org/10.1007/s11033-015-3858-x] [PMID: 25689954]
[17]
Kim J, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006; 3(3): 177-85.
[http://dx.doi.org/10.1016/j.cmet.2006.02.002] [PMID: 16517405]
[18]
Kierans SJ, Taylor CT. Regulation of glycolysis by the hypoxia-inducible factor (HIF): Implications for cellular physiology. J Physiol 2021; 599(1): 23-37.
[http://dx.doi.org/10.1113/JP280572]
[19]
Ou X, Lv W. Metabolic changes and interaction of tumor cell, myeloid-derived suppressor cell and T cell in hypoxic microenvironment. Future Oncol 2020; 16(8): 383-93.
[http://dx.doi.org/10.2217/fon-2019-0692] [PMID: 32067476]
[20]
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144(5): 646-74.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[21]
Kuol N, Stojanovska L, Nurgali K, Apostolopoulos V. PD-1/PD-L1 in disease. Immunotherapy 2018; 10(2): 149-60.
[http://dx.doi.org/10.2217/imt-2017-0120] [PMID: 29260623]
[22]
Ruf M, Moch H, Schraml P. PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma. Int J Cancer 2016; 139(2): 396-403.
[http://dx.doi.org/10.1002/ijc.30077] [PMID: 26945902]
[23]
Corzo CA, Condamine T, Lu L, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 2010; 207(11): 2439-53.
[http://dx.doi.org/10.1084/jem.20100587] [PMID: 20876310]
[24]
Li Y, Patel SP, Roszik J, Qin Y. Hypoxia-driven immunosuppressive metabolites in the tumor microenvironment: New approaches for combinational immunotherapy. Front Immunol 2018; 9: 1591.
[http://dx.doi.org/10.3389/fimmu.2018.01591] [PMID: 30061885]
[25]
Noman MZ, Desantis G, Janji B, et al. PD-L1 is a novel direct target of HIF-1α and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 2014; 211(5): 781-90.
[http://dx.doi.org/10.1084/jem.20131916] [PMID: 24778419]
[26]
Dietl K, Renner K, Dettmer K, et al. Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J Immunol 2010; 184(3): 1200-9.
[http://dx.doi.org/10.4049/jimmunol.0902584] [PMID: 20026743]
[27]
Kumagai S, Koyama S, Itahashi K, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 2022; 40(2): 201-18.
[http://dx.doi.org/10.1016/j.ccell.2022.01.001] [PMID: 35090594]
[28]
Kim S, Jang JY, Koh J, et al. Programmed cell death ligand-1-mediated enhancement of hexokinase 2 expression is inversely related to T-cell effector gene expression in non-small-cell lung cancer. J Exp Clin Cancer Res 2019; 38(1): 462.
[http://dx.doi.org/10.1186/s13046-019-1407-5] [PMID: 31718692]
[29]
Qi J, Nakayama K, Gaitonde S, et al. The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent andindependent pathways. Proc Natl Acad Sci 2008; 105(43): 16713-8.
[http://dx.doi.org/10.1073/pnas.0804063105] [PMID: 18946040]
[30]
Chen J, Hu X, Cui J. Shikonin, vitamin K3 and vitamin K5 inhibit multiple glycolytic enzymes in MCF-7 cells. Oncol Lett 2018; 15(5): 7423-32.
[http://dx.doi.org/10.3892/ol.2018.8251] [PMID: 29725454]
[31]
Oh SJ, Han HK, Kang KW, Lee YJ, Lee MY. Menadione serves as a substrate for P-glycoprotein: Implication in chemosensitizing activity. Arch Pharm Res 2013; 36(4): 509-16.
[http://dx.doi.org/10.1007/s12272-013-0052-3] [PMID: 23435914]
[32]
Miskimins WK, Ahn HJ, Kim JY, Ryu S, Jung YS, Choi JY. Synergistic anti-cancer effect of phenformin and oxamate. PLoS One 2014; 9(1): e85576.
[http://dx.doi.org/10.1371/journal.pone.0085576] [PMID: 24465604]
[33]
Fantin VR, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 2006; 9(6): 425-34.
[http://dx.doi.org/10.1016/j.ccr.2006.04.023] [PMID: 16766262]
[34]
Fiume L, Manerba M, Vettraino M, Di Stefano G. Impairment of aerobic glycolysis by inhibitors of lactic dehydrogenase hinders the growth of human hepatocellular carcinoma cell lines. Pharmacology 2010; 86(3): 157-62.
[http://dx.doi.org/10.1159/000317519] [PMID: 20699632]
[35]
Zhao Z, Han F, Yang S, Wu J, Zhan W. Oxamate-mediated inhibition of lactate dehydrogenase induces protective autophagy in gastric cancer cells: Involvement of the Akt–mTOR signaling pathway. Cancer Lett 2015; 358(1): 17-26.
[http://dx.doi.org/10.1016/j.canlet.2014.11.046] [PMID: 25524555]
[36]
Altinoz MA, Ozpinar A. Oxamate targeting aggressive cancers with special emphasis to brain tumors. Biomed Pharmacother 2022; 147: 112686.
[http://dx.doi.org/10.1016/j.biopha.2022.112686] [PMID: 35124385]
[37]
Jikihara H, Qi G, Nozoe K, et al. Aged garlic extract inhibits 1,2-dimethylhydrazine-induced colon tumor development by suppressing cell proliferation. Oncol Rep 2015; 33(3): 1131-40.
[http://dx.doi.org/10.3892/or.2014.3705] [PMID: 25573280]
[38]
Youssef KM, Ezzo AM, El-Sayed MI, et al. Chemopreventive effects of curcumin analogs in DMH-Induced colon cancer in albino rats model. Fut J Pharmaceut Sci 2015; 1(2): 57-72.
[http://dx.doi.org/10.1016/j.fjps.2015.11.001]
[39]
Gold J. In vivo synergy of vitamin K3 and methotrexate intumor-bearing animals. Cancer Treat Rep 1986; 70(12): 1433-5.
[PMID: 3791255]
[40]
García-Castillo V, López-Urrutia E, Villanueva-Sánchez O, et al.. Targeting metabolic remodeling in triple negative breast cancer in a murine model. J Cancer 2017; 8(2): 178-89.
[http://dx.doi.org/10.7150/jca.16387] [PMID: 28243322]
[41]
El-Sisi AE, Sokar SS, Abu-Risha SE, El-Mahrouk SRJB. Oxamate potentiates taxol chemotherapeutic efficacy in experimentally-induced solid ehrlich carcinoma (SEC) in mice. Pharmacotherapy 2017; 95: 1565-73.
[http://dx.doi.org/10.1016/j.biopha.2017.09.090] [PMID: 28950656]
[42]
Qiao T, Xiong Y, Feng Y, et al. Inhibition of LDH-A by oxamate enhances the efficacy of anti-pd-1 treatment in an nsclc humanized mouse model. Front Oncol 2021; 11(1033): 632364.
[http://dx.doi.org/10.3389/fonc.2021.632364] [PMID: 33859941]
[43]
Banchroft J, Stevens A, Turner D. Theory and practice of histological techniques. Churchil Livingstone, New York, London, San Francisco, Tokyo 1996.
[44]
Phillips T, Murray G, Wakamiya K, et al. Development of standard estrogen and progesterone receptor immunohistochemical assays for selection of patients for antihormonal therapy. Appl Immunohistochem Mol Morphol 2007; 15(3): 325-31.
[http://dx.doi.org/10.1097/01.pai.0000213135.16783.bc] [PMID: 17721279]
[45]
Aman NA, Doukoure B, Koffi KD, et al. Immunohistochemical evaluation of ki-67 and comparison with clinicopathologic factors in breast carcinomas. Asian Pac J Cancer Prev 2019; 20(1): 73-9.
[http://dx.doi.org/10.31557/APJCP.2019.20.1.73] [PMID: 30678383]
[46]
Khan MN, Bhattacharyya T, Andrikopoulos P, et al. Factor inhibiting HIF (FIH-1) promotes renal cancer cell survival by protecting cells from HIF-1α-mediated apoptosis. Br J Cancer 2011; 104(7): 1151-9.
[http://dx.doi.org/10.1038/bjc.2011.73] [PMID: 21386837]
[47]
Skory CD. Isolation and expression of lactate dehydrogenase genes from Rhizopus oryzae. Appl Environ Microbiol 2000; 66(6): 2343-8.
[http://dx.doi.org/10.1128/AEM.66.6.2343-2348.2000] [PMID: 10831409]
[48]
Hassannia H, Ghasemi CM, Atyabi F, et al. Blockage of immune checkpoint molecules increases T-cell priming potential of dendritic cell vaccine. J Nutr Immunol 2020; 159(1): 75-87.
[http://dx.doi.org/10.1111/imm.13126] [PMID: 31587253]
[49]
Abd El Maksoud AI, Taher RF, Gaara AH, et al. Selective regulation of b-raf dependent k-ras/mitogen-activated protein by natural occurring multi-kinase inhibitors in cancer cells. Front Oncol 2019; 9: 1220.
[http://dx.doi.org/10.3389/fonc.2019.01220] [PMID: 31781509]
[50]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[51]
Masoud GN, Li W. HIF-1α pathway: Role, regulation and intervention for cancer therapy. Acta Pharm Sin B 2015; 5(5): 378-89.
[http://dx.doi.org/10.1016/j.apsb.2015.05.007] [PMID: 26579469]
[52]
Porporato PE, Dhup S, Dadhich RK, Copetti T, Sonveaux P. Anticancer targets in the glycolytic metabolism of tumors: A comprehensive review. Front Pharmacol 2011; 2: 49.
[http://dx.doi.org/10.3389/fphar.2011.00049] [PMID: 21904528]
[53]
Semenza GL. Hypoxia‐inducible factors: Coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype. EMBO J 2017; 36(3): 252-9.
[http://dx.doi.org/10.15252/embj.201695204] [PMID: 28007895]
[54]
Nakayama K, Qi J, Ronai Z. The ubiquitin ligase Siah2 and the hypoxia response. Mol Cancer Res 2009; 7(4): 443-51.
[http://dx.doi.org/10.1158/1541-7786.MCR-08-0458] [PMID: 19372575]
[55]
Huang J, Lu Z, Xiao Y, et al. Inhibition of siah2 ubiquitin ligase by vitamin K3 attenuates chronic myeloid leukemia chemo-resistance in hypoxic microenvironment. Med Sci Monit 2018; 24: 727-35.
[http://dx.doi.org/10.12659/MSM.908553] [PMID: 29400343]
[56]
Shah M, Stebbins JL, Dewing A, Qi J, Pellecchia M, Ronai ZA. Inhibition of Siah2 ubiquitin ligase by vitamin K3 (menadione) attenuates hypoxia and MAPK signaling and blocks melanoma tumorigenesis. Pigment Cell Melanoma Res 2009; 22(6): 799-808.
[http://dx.doi.org/10.1111/j.1755-148X.2009.00628.x] [PMID: 19712206]
[57]
Richard DE, Berra E, Pouysségur J. Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. J Biol Chem 2000; 275(35): 26765-71.
[http://dx.doi.org/10.1016/S0021-9258(19)61441-9] [PMID: 10837481]
[58]
Lu H, Forbes RA, Verma A. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 2002; 277(26): 23111-5.
[http://dx.doi.org/10.1074/jbc.M202487200] [PMID: 11943784]
[59]
Miao P, Sheng S, Sun X, Liu J, Huang G. Lactate dehydrogenase a in cancer: A promising target for diagnosis and therapy. IUBMB Life 2013; 65(11): 904-10.
[http://dx.doi.org/10.1002/iub.1216] [PMID: 24265197]
[60]
Verrax J, Vanbever S, Stockis J, Taper H, Calderon PB. Role of glycolysis inhibition and poly(ADP-ribose) polymerase activation in necrotic-like cell death caused by ascorbate/menadione-induced oxidative stress in K562 human chronic myelogenous leukemic cells. Int J Cancer 2007; 120(6): 1192-7.
[http://dx.doi.org/10.1002/ijc.22439] [PMID: 17163414]
[61]
Jayaprakash P, Ai M, Liu A, et al. Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. J Clin Invest 2018; 128(11): 5137-49.
[http://dx.doi.org/10.1172/JCI96268] [PMID: 30188869]
[62]
Li Y, Liang L, Dai W, et al. Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer. Mol Cancer 2016; 15(1): 55.
[http://dx.doi.org/10.1186/s12943-016-0539-x] [PMID: 27552968]
[63]
Shan T, Chen S, Wu T, Yang Y, Li S, Chen X. PD-L1 expression in colon cancer and its relationship with clinical prognosis. Int J Clin Exp Pathol 2019; 12(5): 1764-9.
[PMID: 31933995]
[64]
Lee LH, Cavalcanti MS, Segal NH, et al. Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma. Mod Pathol 2016; 29(11): 1433-42.
[http://dx.doi.org/10.1038/modpathol.2016.139] [PMID: 27443512]
[65]
Wang X, Yang X, Zhang C, et al. Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy. Proc Natl Acad Sci USA 2020; 117(12): 6640-50.
[http://dx.doi.org/10.1073/pnas.1921445117] [PMID: 32161124]
[66]
Zhu Y, Zang Y, Zhao F, et al. Inhibition of HIF-1α by PX-478 suppresses tumor growth of esophageal squamous cell cancerin vitro and in vivo. Am J Cancer Res 2017; 7(5): 1198-212.
[PMID: 28560067]
[67]
Xie H, Valera VA, Merino MJ, et al. LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer. Mol Cancer Ther 2009; 8(3): 626-35.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-1049] [PMID: 19276158]
[68]
Asadi M, Shanehbandi D, Asvadi Kermani T, Sanaat Z, Zafari V, Hashemzadeh S. Expression level of caspase genes in colorectal cancer. Asian Pac J Cancer Prev 2018; 19(5): 1277-80.
[http://dx.doi.org/10.22034/APJCP.2018.19.5.1277] [PMID: 29801534]
[69]
Liu X, Yang Z, Chen Z, et al. Effects of the suppression of lactate dehydrogenase A on the growth and invasion of human gastric cancer cells. Oncol Rep 2015; 33(1): 157-62.
[http://dx.doi.org/10.3892/or.2014.3600] [PMID: 25394466]
[70]
Horváthová J, Moravčík R, Matúšková M, Šišovský V, Boháč A, Zeman M. Inhibition of glycolysis suppresses cell proliferation and tumor progression in vivo: Perspectives for chronotherapy. Int J Mol Sci 2021; 22(9): 4390.
[http://dx.doi.org/10.3390/ijms22094390] [PMID: 33922320]
[71]
Ogawa M, Nakai S, Deguchi A, et al. Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells. Int J Oncol 2007; 31(2): 323-31.
[http://dx.doi.org/10.3892/ijo.31.2.323] [PMID: 17611688]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy