A Novel Dialkylamino-Functionalized Chalcone, DML6, Inhibits Cervical Cancer Cell Proliferation, In Vitro, via Induction of Oxidative Stress, Intrinsic Apoptosis and Mitotic Catastrophe
Jenna M. Len,
Noor Hussein,
Saloni Malla,
Kyle Mcintosh,
Rahul Patidar,
Manivannan Elangovan,
Karthikeyan Chandrabose,
N. S. Hari Narayana Moorthy,
Manoj Pandey,
Dayanidhi Raman,
Piyush Trivedi,
Amit K. Tiwari
Affiliations
Jenna M. Len
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
Noor Hussein
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
Saloni Malla
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
Kyle Mcintosh
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
Rahul Patidar
School of Pharmacy, Devi Ahilya Vishwavidyalaya, Indore 452001, India
Manivannan Elangovan
School of Pharmacy, Devi Ahilya Vishwavidyalaya, Indore 452001, India
Karthikeyan Chandrabose
Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak 484887, India
N. S. Hari Narayana Moorthy
Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak 484887, India
Manoj Pandey
Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
Dayanidhi Raman
Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
Piyush Trivedi
Center of Innovation and Translational Research, Poona College of Pharmacy, Bhartiya Vidyapeeth, Pune 411038, India
Amit K. Tiwari
Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
In this study, we designed, synthesized and evaluated, in vitro, novel chalcone analogs containing dialkylamino pharmacophores in the cervical cancer cell line, OV2008. The compound, DML6 was selective and significantly decreased the proliferation of OV2008 and HeLa cells in sub-micromolar concentrations, compared to prostate, lung, colon, breast or human embryonic kidney cell line (HEK293). DML6, at 5 μM, arrested the OV2008 cells in the G2 phase. Furthermore, DML6, at 5 μM, increased the levels of reactive oxygen species and induced a collapse in the mitochondrial membrane potential, compared to OV2008 cells incubated with a vehicle. DML6, at 5 μM, induced intrinsic apoptosis by significantly (1) increasing the levels of the pro-apoptotic proteins, Bak and Bax, and (2) decreasing the levels of l the anti-apoptotic protein, Bcl-2, compared to cell incubated with a vehicle. Furthermore, DML6, at 5 and 20 μM, induced the cleavage of caspase-9, followed by subsequent cleavage of the executioner caspases, caspase-3 and caspase-7, which produced OV2008 cell death. Overall, our data suggest that DML6 is an apoptosis-inducing compound that should undergo further evaluation as a potential treatment for cervical cancer.