β-Lapachone and its iodine derivatives cause cell cycle arrest at G2/M phase and reactive oxygen species-mediated apoptosis in human oral squamous cell carcinoma cells.

β-Lapachone is a natural naphthoquinone originally obtained from the bark of the purple Ipe (Tabebuia avellanedae Lor, Bignoniaceae) and its therapeutic potential in human cancer cells has been evaluated in several studies. In this study, we examined the effects of β-lapachone and its 3-iodine derivatives (3-I-α-lapachone and 3-I-β-lapachone) on cell proliferation, cell death, and cancer-related gene expression in human oral squamous cell carcinoma cells. β-Lapachone and its 3-iodine derivatives showed potent cytotoxicity against different types of human cancer cell lines. Indeed, treatment with these compounds induced cell cycle arrest at G2/M phase, followed by internucleosomal DNA fragmentation, and caused significant increases in phosphatidylserine externalization, caspase-8 and -9 activation, mitochondrial membrane depolarization, reactive oxygen species (ROS) production, and apoptotic cell death morphology. The apoptosis induced by the compounds was prevented by pretreatment with a pan-caspase inhibitor (Z-VAD-FMK) and an antioxidant (N-acetyl-l-cysteine). In vivo, β-lapachone and its 3-iodine derivatives significantly reduced tumor burden and did not alter any of the biochemical, hematological, or histological parameters of the animals. Overall, β-lapachone and its 3-iodine derivatives showed promising cytotoxic activity due to their ability to induce cell cycle arrest at G2/M phase and promote caspase- and ROS-mediated apoptosis. In addition, β-lapachone and its 3-iodine derivatives were able to suppress tumor growth in vivo, indicating that these compounds may be new antitumor drug candidates.