Background: Cancer is the second leading cause of death worldwide and each year tens of millions of people are lost their lives due to different types of cancer. Despite all efforts in the treatment of cancer, the mortality and morbidity rates are still in high levels. Multidrug resistance (MDR) is one of the main impediments in the cancer treatment. MDR might result in tumor metastasis and recurrence, which is responsible for 90% of cancer-related deaths. Many intrinsic and extrinsic factors such as genetic and epigenetic modifications, drug efflux systems, DNA repair mechanisms, apoptotic and autophagic processes contribute drug resistance in cancer cells. To date, various types of molecules have been tested in vitro and in vivo, for MDR modulating activity but there is still no effective anticancer drug to completely overcome MDR. Phytochemicals, in alone or in combination with other chemotherapeutics, are potentially able to sensitize the cancer cells to conventional anticancer drugs in cancer patients with fewer side effects. In this review, we aimed to provide a general perspective about MDR-related mechanisms and novel therapeutic approaches including RNA interference (RNAi) therapy, nanotherapy and cancer stem cell treatments to combat MDR and to highlight the latest MDR reversing agents of plant origin based on their modulating effects on various proteins, enzymes, transcription factors, cell cycle regulators and survival and oncogenic pathways.
Conclusion: Plant-derived secondary metabolites may improve the therapeutic efficacy of anticancer drugs through targeting different MDR-related mechanisms and they serve as lead compounds to elicit better pharmacological results in the development of novel anticancer agents.