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The Anti-Proliferative Activity of the Hybrid TMS-TMF-4f Compound Against Human Cervical Cancer Involves Apoptosis Mediated by STAT3 Inactivation

1
Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea
2
Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea
3
Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea
4
Medicinal Chemistry Laboratory, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea
5
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
6
KHU-KIST Department of Converging Science and Technology, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this study.
Cancers 2019, 11(12), 1927; https://doi.org/10.3390/cancers11121927
Received: 2 October 2019 / Revised: 18 November 2019 / Accepted: 28 November 2019 / Published: 3 December 2019
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.
Keywords: TMS-TMF-4f; human cervical cancer; STAT3; apoptosis; xenograft TMS-TMF-4f; human cervical cancer; STAT3; apoptosis; xenograft
MDPI and ACS Style

Hong, J.Y.; Chung, K.-S.; Shin, J.-S.; Lee, J.-H.; Gil, H.-S.; Lee, H.-H.; Choi, E.; Choi, J.-H.; Hassan, A.H.; Lee, Y.S.; Lee, K.-T. The Anti-Proliferative Activity of the Hybrid TMS-TMF-4f Compound Against Human Cervical Cancer Involves Apoptosis Mediated by STAT3 Inactivation. Cancers 2019, 11, 1927.

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