Zakaria Sherin, Elsebaey Samar, Allam Shady, Abdo Walied, El-Sisi Alaa
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kaferelsheikh University, 33516, Kaferelsheikh, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Menoufia University, 32511, Menoufia, Egypt.
Recent Pat Anticancer Drug Discov. 2023 Jan 16. doi: 10.2174/1574892818666230116142606.
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.
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.
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.
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.
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].
结肠癌等实体瘤的特征是细胞快速持续增殖，最终导致缺氧、缺氧诱导因子-1α（HIF-1α）的诱导以及糖酵解的激活，以促进肿瘤存活和免疫逃逸。我们假设，以甲萘醌（MEN）作为间接HIF-1α抑制剂和草氨酸钠（OX）作为糖酵解抑制剂的联合方法可能是一种有前景的结肠癌治疗策略。
我们研究了这种联合用药在促进结肠癌大鼠模型中的抗肿瘤免疫反应和抑制肿瘤生长方面的潜在疗效。
通过每周一次皮下注射20mg/kg二甲基肼（DMH），持续16周诱导结肠癌。对照大鼠接受赋形剂，然后不再接受进一步治疗（阴性对照）或接受MEN加OX治疗4周（药物对照）。然后将经二甲基肼处理的大鼠随机分为四组：单独使用DMH组和其他分别用MEN、OX以及MEN与OX联合治疗4周的组。检测血清样本中的肿瘤标志物糖类抗原（CA19.9），同时通过免疫测定和qRT-PCR评估结肠组织样本中HIF-1α、半胱天冬酶-3、PHD3、乳酸脱氢酶（LDH）和程序性死亡受体1（PD1）的表达水平。此外，通过免疫组织化学检测Ki-67和Siah2的表达水平。
与单独使用任何一种药物相比，MEN加OX的联合用药对结肠癌组织中HIF-1α、Siah2、LDH、Ki-67和PD1的表达水平具有更大的抑制作用，并且对半胱天冬酶-3和PHD3表达的增强作用更大。
MEN和OX联合同时靶向缺氧和糖酵解途径可能是一种有前景的抑制结肠癌细胞生长和促进抗肿瘤免疫的治疗方法[1]。
