Abstract
We previously reported the potential anti-proliferative activity of 3-(5,6,7-trimethoxy-4-oxo-4H-chromen-2-yl)-N-(3,4,5-trimethoxyphenyl) benzamide (TMS-TMF-4f) against human cancer cells; however, the underlying molecular mechanisms have not been investigated. In the present study, TMS-TMF-4f showed the highest cytotoxicity in human cervical cancer cells (HeLa and CaSki) and low cytotoxicity in normal ovarian epithelial cells. Annexin V-FITC and propidium iodide (PI) double staining revealed that TMS-TMF-4f-induced cytotoxicity was caused by the induction of apoptosis in both HeLa and CaSki cervical cancer cells. The compound TMS-TMF-4f enhanced the activation of caspase-3, caspase-8, and caspase-9 and regulated Bcl-2 family proteins, which led to mitochondrial membrane potential (MMP) loss and resulted in the release of cytochrome c and Smac/DIABLO into the cytosol. Also, TMS-TMF-4f suppressed both constitutive and IL-6-inducible levels of phosphorylated STAT3 (p-STAT3) and associated proteins such as Mcl-1, cyclin D1, survivin, and c-Myc in both cervical cancer cells. STAT-3 overexpression completely ameliorated TMS-TMF-4f-induced apoptotic cell death and PARP cleavage. Docking analysis revealed that TMS-TMF-4f could bind to unphosphorylated STAT3 and inhibit its interconversion to the activated form. Notably, intraperitoneal administration of TMS-TMF-4f (5, 10, or 20 mg/kg) decreased tumor growth in a xenograft cervical cancer mouse model, demonstrated by the increase in TUNEL staining and PARP cleavage and the reduction in p-STAT3, Mcl-1, cyclin D1, survivin, and c-Myc expression levels in tumor tissues. Taken together, our results suggest that TMS-TMF-4f may potentially inhibit human cervical tumor growth through the induction of apoptosis via STAT3 suppression.
Highlights
Cervical cancer is a major gynecologic cancer worldwide, ranked as the fourth most frequently occurring cancer among women and characterized by a 30% mortality rate within five years of treatment [1]
We evaluated the effect of these synthetic hybrids on the viability of on the viability of other five human by cancer cells and investigated their underlying molecular mechanisms, which mayinbe mediated the suppression of STAT3 activation in human cervical cancer cells in vitro and vivo
STAT3 activation in cervical cancer proliferation [26], we examined the effects of TMS-TMF-4f on STAT3 activation in cervical cancer cells
Summary
Cervical cancer is a major gynecologic cancer worldwide, ranked as the fourth most frequently occurring cancer among women and characterized by a 30% mortality rate within five years of treatment [1]. Around 90% of cervical cancer cases are squamous cell carcinomas, and 10% of cases are adenocarcinomas with a small number of cases involving other types of carcinomas [4]. Standard treatments such as surgery and combination of chemotherapy and radiotherapy have significantly improved the clinical outcomes of cervical cancer patients in early stages, the clinical management of cervical cancer in advanced stages remains a challenge. Chemotherapies using platinum and taxol are still standard therapeutic approaches; the outcomes are not satisfactory, especially for patients with chemoresistance [1]
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