Piperine synergistically enhances the effect of temozolomide against temozolomide-resistant human glioma cell lines

Temozolomide (TMZ) is an alkylating chemotherapy agent used in the clinical treatment of glioblastoma multiforme (GBM) patients. Piperine (PIP) is a naturally occurring pungent nitrogenous substance present in the fruits of peppers. We investigated the anti-cancer efficacies of PIP alone and in combination with TMZ in GBM cellsusingparameters such as cell proliferation, cellular apoptosis,caspase-8/-9/-3 activities, cell cycle kinetics, wound-healing ability, and loss of mitochondrial membrane potential (MMP). Treatment with PIP and alow concentration of PIP-TMZ, inhibited cell growth, similar to TMZ.PIP-TMZ promoted apoptosis by activation of caspase-8/-9/-3, MMP loss, and inhibition ofin vitrowound-healing motility. Reverse transcription polymerase chain reaction analysis showed significant inhibition ofCyclin-dependent kinases(CDK)4/6-cyclin DandCDK2-cyclin-Eexpression upon treatment with a low concentration PIP-TMZ, suggesting an S to G1 arrest. Our findings provide insight into the apoptotic potential of the combination of a low concentration of PIP-TMZ, though furtherin vivostudy will be needed for its validation.