Abstract
Multidrug resistance (MDR) is a critical problem in cancer chemotherapy. Cancer cells can develop resistance not only to a single cytotoxic drug, but also to entire classes of structurally and functionally unrelated compounds. Several mechanisms can mediate the development of MDR, including increased drug efflux from the cells by ABC-transporters (ABCT), activation of metabolic enzymes, and defective pathways towards apoptosis. Many plant secondary metabolites (SMs) can potentially increase sensitivity of drug-resistant cancer cells to chemotherapeutical agents. The present thesis investigates the modulation of MDR by certain medicinal plants and their active compounds. The inhibition of ABCTs (P-gp/MDR1, MRP1, BCRP) and metabolic enzymes (GST and CYP3A4), and the induction of apoptosis are useful indicators of the efficacy of a potential medicinal drug. The focus of this study was the possible mechanisms of drug resistance including: expression of resistance proteins, activation of metabolic enzymes, and alteration of the apoptosis and how to overcome their resistance effect on cancer cells. The overall goal of this review was to evaluate how commonly used medicinal plants and their main active secondary metabolites modulate multidrug resistance in cancer cells in order to validate their uses as anticancer drugs, introduce new therapeutic options for resistant cancer, and facilitate the development of their anticancer strategies and/or combination therapies. In conclusion, SMs from medicinal plants exhibit multitarget activity against MDR-related proteins, metabolic enzymes, and apoptotic signaling, this may help to overcome resistance towards chemotherapeutic drugs.
Highlights
Cancer is the second leading cause of death, after heart disease, killing about every fifth or sixth person in western countries
Studies find that many substrates of MDR1 are substrates of drug-metabolizing enzymes, such as CYP3A4. This overlap may be to some extent a result of a coordinated regulation of tissue expression of CYP3A4 and MDR1 in organs such as the liver and intestine [56]
Second hypothesis is that multidrug resistance (MDR) expression alters intracellular pH, which contributes to MDR1 gaining resistance to several forms of caspase-dependant cell death stimuli resulting in lower drug concentrations
Summary
Cancer is the second leading cause of death, after heart disease, killing about every fifth or sixth person in western countries. Of the 14.1 million new cases each year, more than half occur in developing countries and 32.5 million persons are alive with cancer [1]. Cancer is defined as a disease in which normal tissue is invaded by abnormally dividing cells. Left untreated, it will spread throughout the body and becomes fatal. Chemotherapy (the use of cytotoxic agents to slow the progression of this uncontrolled cell division) is the major treatment when cancer is well established within the patient [2]. Resistance to anticancer drugs is a major problem in chemotherapy with 30% - 80% of cancer patients developing resistance to chemotherapeutical drugs [3]. Counteracting drug resistance is crucial to providing the best treatment
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