Inhibition of cell cycle and apoptosis in human cervix carcinoma cell lines induced by rhein, quercetin and plumbagin and in silico designed semi synthetic analogs

Increasing epidemiological and experimental evidences indicate that natural polyphenols are interesting substances in chemoprevention, a new approach to develop efficient strategies of controlling cancer (1). We studied the effect of rhein (antraquinone), quercetin (flavonoid) and plumbagin (naphtoquinone) on wild type (A431) human cervix carcinoma cells line and on cis-platin (CDDP) resistant variant (A431Pt). Cells were treated for 24 hours with (0.1mM– 0.1mM) of different natural phenols and cytotoxicity and cell cycle were measured. Results demonstrate that all substances were cytotoxic at micromolar concentration, also causing evident alterations of cell cycle phases and apoptosis. In order to test the likely mechanism of inhibition of cell cycle by natural phenols an hightroughput consensus docking study with ATP-binding pocket of cdk2 protein kinase was performed. Results evidence that some small derivatives of antraquinones, flavonoids and naphtoquinones have likely improved affinity for ATP-binding cleft of cdk2. These derivatives were synthetized and their effects at concentrations (0.1mM– 0.1mM) were assayed on cell viability and cell cycle in cervix carcinoma cell lines. Results show that semisynthetic naphtaquinones are more potent cytotoxic compounds than antraquinones and flavonoid analogs, causing cell cycle alterations and apoptosis. Data support natural phenols as chemosensitizing cytotoxic substances (2) and also that in silico design of new phenols derivatives is an useful approach to obtain more selective targeted compounds in cancer therapy.