Abstract
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.
Highlights
Cervical cancer is the fourth-leading cause of cancer-related deaths in women worldwide resulting in an estimated 600,000 new cervical cancer cases and 342,000 deaths, yearly [1]
Our results indicate that 20 μM of DML6 significantly decreased (p < 0.01) the levels of the anti-apoptotic protein, Bcl-2, and 5 and 20 μM of DML6 significantly increased the expression of the pro-apoptotic proteins, Bax (p < 0.05) and Bak (p < 0.01)
A series of 12 novel chalcone derivatives were designed, synthesized and characterized. After screening these compounds in a panel of cancer cell lines to determine their anti-proliferative efficacy, DML6, had the highest in vitro efficacy, with an IC50 value of 7.8 μM and had selectivity for inducing cytotoxicity in the cervical carcinoma cell line, OV2008 compared to other epithelial cancer cells i.e., HEK293, LOVO, MDAMB-231, DU145 and A549
Summary
Cervical cancer is the fourth-leading cause of cancer-related deaths in women worldwide resulting in an estimated 600,000 new cervical cancer cases and 342,000 deaths, yearly [1]. Women with locally advanced cervical carcinoma have worse prognosis, poor survival and higher recurrence rate than patients with early-staged cervical cancer [12,13]. Chemoresistance is the most important factor that decreases or abrogates the efficacy of chemotherapy in many cancers including advanced cervical cancer, producing an increase in tumor progression, which results in high rates of cancer-related deaths [16,17]. Many chalcone derivatives have been synthesized and shown to be efficacious in vitro and in vivo in various cancer cells [20,23]. In this study, we report the synthesis of novel chalcones and their 4,5-dihydro-1H-pyrazoles analogues containing the dialkylamine and their in vitro efficacy in various cancer cell lines. ScShcehmeme e1.1R. eRaegaegnetnstasnadndcocnodnidtiiotinosn:s(:a()a4)04%0%aqauqeuoeuosuNs NaOaHOH, E,tEOtHO,HR,TR, Tst,isrtriirnrgin; g(b; )(bC)6CH65HN5NHHNNHH2,2, CSCHchH3eC3mCOOeOO1H.H,Rr,eeraflegfuleuxn,xt6,s6ha.nhd. conditions: (a) 40% aqueous NaOH, EtOH, RT, stirring; (b) C6H5NHNH2, CH3COOH, reflux, 6 h
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