Curcumin Enhances the Anti-Cancer Efficacy of CDK4/6 Inhibitors in Prostate Cancer.

OBJECTIVE: This study aimed to investigate the potential of combining cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors with curcumin (Cur), a natural compound known for its anti-aging properties, to enhance the anti-cancer efficacy in prostate cancer (PCa).

METHODS: The cell viability was determined by cell counting kit-8 assay, colony forming assay and cell invasion. The cell cycle and mRNA levels of p16 (cyclin dependent kinase inhibitor 2A, CDKN2A), p21 (cyclin dependent kinase inhibitor 1A, CDKN1A) and Rb (RB transcriptional corepressor) were detected by flow cytometry and quantitative real-time polymerase chain reaction, respectively. SA-β-gal staining and interleukin 6 (IL6) mRNA levels were used to evaluate cell aging. Western blot was used to detect mechanistic targets of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) pathways. Moreover, Sphere formation assay and mRNA levels of aldehyde dehydrogenase (ALDH) 1A1, CD44 and Nanog were used to determine cell stemness.

RESULTS: The combination of LY2835219 (LY, CDK4/6 inhibitor) and Cur exhibited a synergistic inhibitory effect on PCa cell proliferation ( p < 0.01) and invasion ( p < 0.01) and Rb gene expression ( p < 0.05), as well as a synergistic promotive effect on p61 expression ( p < 0.01), p21 expression ( p < 0.01) and cell cycle G1 arrest in PCa cells ( p < 0.05) compared with LY or Cur alone. LY and LY + Cur increased the SA-β-gal-stained cells ( p < 0.01). mTOR ( p < 0.01) and STAT3 pathway ( p < 0.01) were decreased by LY + Cur ( p < 0.01). Furthermore, LY + Cur conditioned medium (CM) inhibited cell stemness by decreasing cell spheres ( p < 0.05), ALDH1A1 ( p < 0.01), CD44 ( p < 0.01) and Nanog ( p < 0.01) compared with LY CM.

CONCLUSIONS: The findings of this study suggested that the combination of CDK4/6 inhibitor and curcumin may have clinical implications for the treatment of PCa.