Siah2 inhibitor and the metabolic antagonist Oxamate retard colon cancer progression and downregulate PD1 expression.

Autor:	Zakaria S; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kaferelsheikh University, 33516, Kaferelsheikh, Egypt., Elsebaey S; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kaferelsheikh University, 33516, Kaferelsheikh, Egypt., Allam S; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Menoufia University, 32511, Menoufia, Egypt., Abdo W; Department of Pathology, Faculty of Veterinary Medicine, Kafrelsheikh University, 33516 Kaferelsheikh, Egypt., El-Sisi A; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, 31512, Tanta, Egypt.
Jazyk:	angličtina
Zdroj:	Recent patents on anti-cancer drug discovery [Recent Pat Anticancer Drug Discov] 2023 Jan 16. Date of Electronic Publication: 2023 Jan 16.
DOI:	10.2174/1574892818666230116142606
Abstrakt:	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 [1]. (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
Databáze:	MEDLINE
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