Polymethoxy-/polyacetyl-flavones cytotoxicity towards colorectal and prostate cancer cell lines: SAR, mechanisms of action and evaluation as potential adjuvants in chemotherapy.

A set of natural and semi-synthetic polymethoxy- and polyacetyl-flavones (PMFs/PAFs) was evaluated towards colorectal (HCT116) and prostate (PC-3) cancer cells. The most active compounds were then combined with 5-fluorouracil (5-FU) or with adriamycin (ADR) in order to determine a potential synergism, focusing on contingent changes in cell cycle and apoptosis. Two derivatives were strongly cytotoxic. They also induced G0/G1 cell cycle arrest, but differently behaved when combined to the reference drugs 5-FU or ADR. The induction of apoptosis was stronger towards HCT116, noticeably increasing the activity of 5-FU, suggesting a potential additive effect. Besides, the results of soluble caspase-cleaved K18 showed that another phenomenon such as autophagy may be involved towards PC-3 cells and should be deciphered. Consequently, these two PMFs are considered as suitable candidates for further studies in hit-to‑lead approach, in a context of a therapeutic protocol involving natural products as chemosensitizers, aiming to increase the potency and to reduce the side effects of antitumor drugs.