Multiple Molecular Mechanisms to Overcome Multidrug Resistance in Cancer by Natural Secondary Metabolites

Plant secondary metabolites (SMs) common natural occurrences and the significantly lower toxicities of many SM have led to the approaching development and use of these compounds as effective pharmaceutical agents; especially in cancer therapy. A combination of two or three plant secondary metabolites together or of one SM with specific anticancer drugs may synergistically decrease the doses needed, widen the chemotherapeutic window, mediate more effective cell growth inhibition, and avoid the side effects of high drug concentrations. In mixtures, they can exert additive or even synergistic activities. Many SM can effectively increase the sensitivity of cancer cells to chemotherapy. In phytotherapy, secondary metabolites (SM) of medicinal plants can interact with single or multiple targets. The multi-molecular mechanisms of plant secondary metabolites to overcome multidrug resistance (MDR) are highlighted in this review. These mechanisms include interaction with membrane proteins such as P-glycoprotein (P-gp/MDR1); an ATP-binding cassette (ABC) transporter, nucleic acids (DNA, RNA), and induction of apoptosis. P-gp plays an important role in the development of MDR in cancer cells and is involved in potential chemotherapy failure. Therefore, the ingestion of dietary supplements, food or beverages containing secondary metabolites e.g., polyphenols or terpenoids may alter the bioavailability, therapeutic efficacy and safety of the drugs that are P-gp substrates.