Deciphering the molecular mechanism and apoptosis underlying the in-vitro and in-vivo chemotherapeutic efficacy of vanadium luteolin complex in colon cancer

Abstract

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.

Significance: 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.

Keywords: DNA binding; colon carcinogenesis; in-vitro study; toxicity study; vanadium luteolin complex.