Mechanisms of Multidrug Resistance in Cancer Chemotherapy

Abstract

Cancer is one of the main causes of death worldwide. Despite the significant development of methods of cancer healing during the past decades, chemotherapy still remains the main method for cancer treatment. Depending on the mechanism of action, commonly used chemotherapeutic agents can be divided into several classes (antimetabolites, alkylating agents, mitotic spindle inhibitors, topoisomerase inhibitors, and others). Multidrug resistance (MDR) is responsible for over 90% of deaths in cancer patients receiving traditional chemotherapeutics or novel targeted drugs. The mechanisms of MDR include elevated metabolism of xenobiotics, enhanced efflux of drugs, growth factors, increased DNA repair capacity, and genetic factors (gene mutations, amplifications, and epigenetic alterations). Rapidly increasing numbers of biomedical studies are focused on designing chemotherapeutics that are able to evade or reverse MDR. The aim of this review is not only to demonstrate the latest data on the mechanisms of cellular resistance to anticancer agents currently used in clinical treatment but also to present the mechanisms of action of novel potential antitumor drugs which have been designed to overcome these resistance mechanisms. Better understanding of the mechanisms of MDR and targets of novel chemotherapy agents should provide guidance for future research concerning new effective strategies in cancer treatment.

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

“…Impediments to apoptosis, reducing drug accumulation, alterations in cell cycle and enhancement of the tumor energy supply are the main reasons for MDR. Increases in DNA repair capacity, checkpoint changes, the presence of CSCs in tumors, gene mutations (PTEN mutations or disappearance, mutations in the TP53 gene), changes in drug target separation and epithelial-mesenchymal transition are also related to MDR [133][134][135] . These mechanisms must be carefully discussed in the future.…”

Irinotecan—Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview

“…These include the use of liposomal formulations, dendrimers, and nanoparticles as delivery systems. Among conventional antineoplastic drugs, several classes are distinguishable: alkylating agents, antimetabolites, topoisomerase inhibitors, mitotic spindle inhibitors, and others [ 2 , 3 ]. Topoisomerase I inhibitors have been extensively studied since the late 1960s; however, initially, their clinical use was hindered due to their severe toxicity and low stability.…”

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

“…Thus, MDR is a public health problem that requests an urgent solution. However, overcoming MDR in cancer is one of the foremost challenges in the present therapeutic era since MDR is a multifactorial phenomenon involving many different mechanisms, such as over-expression of ATP-binding cassette ABC protein transporters that increased the efflux of chemotherapeutic drugs, enhanced DNA damage repair, mutation of oncogenes that become resistant to former treatments, adaptation of cancer cells to the tumor microenvironment, surviving of cancer stem cells that escape from conventional therapies, among others [ 3 , 4 , 5 , 6 ].…”