Antitumor Mechanism Of Chloromethylene Thiochromanone Derivatives In Vitro

Thiochromanones is one class of compounds with extensive biological activities. Ourlaboratory has synthesized a variety of thiochromanone derivatives, and these chemicals werecertified to have anti-tumor activities. Until now, their anti-tumor mechanism is poorlyunderstood. Here, we choosed two Chloromethylene thiochromanones compounds withhigher antitumor activities,(Z)-3-(chloromethylene)-6-methylthiochroman-4-one(CMMT)and (Z)-3-(chloromethylene)-6-chlorinthiochroman-4-one (CMCT) as Representativecompounds to explore their antitumor mechanism in vitro.HepG-2and Hela cells were selected as experimental subjects. The effect of CMCT andCMMT on cell proliferation, apoptosis induction, and morphology changes were detectedwith corresponding method in these two celllines; The expression levels of TNFR1,Caspase-3, Caspase-8and Caspase-9protein were detected by ELISA. The results showedthat CMCT and CMMT induced apoptosis on HepG-2and Hela cells in dose-dependentmanner. CMMT activated Caspase-3, Caspase-8, Caspase-9, TNFR1and DR3. Adjusted theexpression of Bax, Bcl-2and p53genes. It is interesting that apoptosis-inducing gene wereincreased and apoptosis-inhibiting gene Bcl-2was decreased. These results suggested thatCMMT induced apoptosis of Hela and HepG-2cells via death receptor pathway andmitochondrial-dependent pathway.We also detected the immune activation effect of CMMT by using mice originalmacrophages. The result showed CMMT had LPS-like effect, can activated micemacrophages to increase production of TNF-α、IL-6、IL-12. It means that the antineoplasticeffect of CMMT may be contributed partly by strengthening the immune system function.