Department of Pharmaceutical Technology, NSHM Knowledge Campus-Kolkata, Group of Institutions, Kolkata, West Bengal, India.
Cell Biochem Funct. 2018 Apr;36(3):116-128. doi: 10.1002/cbf.3322. Epub 2018 Mar 25.
The present study is carried out to reveal the chemotherapeutic effects of vanadium luteolin complex against HT-29 human colon carcinoma cell line and chemically induced rat colon carcinoma. Our investigation revealed that the vanadium luteolin complex induces apoptosis in HT-29 cells in a dose-dependent manner. Furthermore, the study also confirmed that the vanadium luteolin complex increased caspase-3 and p53 expression whereas reduced the VEGF, mTOR, Akt expression, and induced DNA fragmentation in HT-29 cells. The oral acute and sub-acute toxicity and the DNA binding efficacy of the complex with CT-DNA were investigated. The vanadium luteolin complex showed mortality at a dose of 120 mg/kg dose. The sub-acute toxicity of the complex at the dose of 90 mg/kg presented an increased level of WBC count, total bilirubin, ALT, AST, ALP, creatinine, blood urea nitrogen, and decreased level of total protein compared with the control group. Histopathological alterations in kidney, liver, stomach, and lungs was observed at a dose of 90 mg/kg of the complex. The dose of 45 mg/kg of the complex was found to have better chemotherapeutic activity by significantly reducing the incidences of aberrant crypt foci formation, upregulation in the expression of p53 and Bax, and downregulation of the expression of Bcl2, and cell proliferation was found in the complex at a dose of 45 mg/kg. Our findings from the study support that the complex possesses a potential chemotherapeutic activity against colon cancer and was efficient in reducing aberrant crypt foci formation multiplicity, hyperplastic lesions in the colon tissues of rats by inducing apoptosis.
The present study demonstrates that the effect of vanadium-luteolin complex in HT-29 cells and dimethylhydrazine challenged rats, curtail cell proliferation through induction of apoptosis mediated via activation of the key proteins involved in the intrinsic pathway like p53, Bax, caspase-3 and downregulating Bcl2, mTOR/Akt, angiogenic factor VEGF along with aberrant crypt foci formation multiplicity, and PCNA in the colon mucosa. Our combinatorial approach shows higher efficacy at considerably lower doses minimizing side effects. Insights into in-vitro and in-vivo results provide strong proof that low dose chemotherapeutic regimens can suppress, reverse, or delay the progression of colon cancer by modulating intrinsic apoptotic as well as antiangiogenic pathways.
本研究旨在揭示钒-芦丁络合物对 HT-29 人结肠癌细胞系和化学诱导的大鼠结肠癌的化疗作用。我们的研究表明，钒-芦丁络合物以剂量依赖的方式诱导 HT-29 细胞凋亡。此外，该研究还证实，钒-芦丁络合物增加了 caspase-3 和 p53 的表达，而降低了 VEGF、mTOR、Akt 的表达，并诱导了 HT-29 细胞的 DNA 片段化。研究了复合物的口服急性和亚急性毒性以及与 CT-DNA 的 DNA 结合效力。钒-芦丁络合物在 120mg/kg 剂量下表现出致死性。在 90mg/kg 剂量下，复合物的亚急性毒性与对照组相比，白细胞计数、总胆红素、ALT、AST、ALP、肌酐、血尿素氮升高，总蛋白水平降低。在 90mg/kg 剂量下，复合物观察到肾脏、肝脏、胃和肺部的组织病理学改变。在 45mg/kg 剂量下，复合物具有更好的化疗活性，通过显著降低异常隐窝形成的发生率、上调 p53 和 Bax 的表达以及下调 Bcl2 的表达，同时发现复合物在 45mg/kg 剂量下具有细胞增殖作用。本研究结果支持该络合物具有治疗结肠癌的潜力，并能有效减少结肠组织中异常隐窝形成的多发性、增生性病变，通过诱导凋亡来抑制细胞增殖。
本研究表明，钒-芦丁络合物在 HT-29 细胞和二甲基肼挑战大鼠中的作用，通过激活参与内在途径的关键蛋白，如 p53、Bax、caspase-3 并下调 Bcl2、mTOR/Akt、血管生成因子 VEGF 以及异常隐窝形成的多发性和结肠黏膜中的 PCNA，来抑制细胞增殖，从而诱导细胞凋亡。我们的组合方法在使用低得多的剂量时显示出更高的疗效，同时最大限度地减少副作用。体内和体内结果的深入了解提供了强有力的证据，证明低剂量化疗方案可以通过调节内在凋亡和抗血管生成途径来抑制、逆转或延缓结肠癌的进展。
