Multidrug Resistance in Cancer: Understanding Molecular Mechanisms, Immunoprevention and Therapeutic Approaches

Abstract

Cancer is one of the leading causes of death worldwide. Several treatments are available for cancer treatment, but many treatment methods are ineffective against multidrug-resistant cancer. Multidrug resistance (MDR) represents a major obstacle to effective therapeutic interventions against cancer. This review describes the known MDR mechanisms in cancer cells and discusses ongoing laboratory approaches and novel therapeutic strategies that aim to inhibit, circumvent, or reverse MDR development in various cancer types. In this review, we discuss both intrinsic and acquired drug resistance, in addition to highlighting hypoxia- and autophagy-mediated drug resistance mechanisms. Several factors, including individual genetic differences, such as mutations, altered epigenetics, enhanced drug efflux, cell death inhibition, and various other molecular and cellular mechanisms, are responsible for the development of resistance against anticancer agents. Drug resistance can also depend on cellular autophagic and hypoxic status. The expression of drug-resistant genes and the regulatory mechanisms that determine drug resistance are also discussed. Methods to circumvent MDR, including immunoprevention, the use of microparticles and nanomedicine might result in better strategies for fighting cancer.

Keywords: cancer; immuno-prevention; intracellular and extracellular ATP; microRNA; multidrug resistance.

Figure 1

Schematic presentation of possible drug resistance mechanisms in cancer. Cancer cells develop resistance to anticancer agents (drugs) through various mechanisms, such as diminished drug uptake, enhanced drug efflux, improved DNA damage repair, resistance to cellular senescence (apoptosis suppression), alteration of drug metabolism, alteration of the drug target, epigenetic changes, and target gene amplification. These mechanisms act either individually or in combination, leading to the development of single or multidrug resistance in cancer cells (M, methylation; dM, demethylation).

Figure 2

Various potential mechanisms contribute to multidrug resistance. Many internal and external factors have been associated with the development of multidrug resistance in human cancer cells through either direct or indirect effects. Drug efflux, changes in cellular drug levels, drug inactivation, altered epigenetic states, epithelial–mesenchymal transition (EMT), the tumor microenvironment, DNA damage repair, cancer stem cell propagation, and immune system evasion are well-studied mechanisms thought to contribute to MDR through various signal transduction pathways, either independently or in combination.

Figure 3

An overview of drug resistance mechanisms in cancer cells using ABC transporter, LRP, Bcl-2, and Topo ll. The ATP-binding cassette (ABC) transporter is an ATP-activated transporter. In general chemotherapy, cells express ABC transporters to remove foreign molecules (e.g., xenobiotics, anticancer agents, etc.) from the intracellular environment. P-glycoprotein (P-gp), multidrug-resistant protein 1 (MRP-1), and breast cancer resistance protein (BCRP) are the predominant members of the ABC transporter family. Lung resistance protein (LRP) resides in vaults (cytoplasmic) and contributes to the exocytosis of foreign molecules, including anticancer drugs. Research also revealed that the upregulation of bcl-2 (an anti-apoptotic factor acted upon by anticancer agents that activate the normal apoptosis process), p53 loss-of-function of p53, and the downregulation of topoisomerase II (Topo-II) also decrease cell apoptosis to increase the resistance of cancer cells to anticancer drugs (74).

Figure 4

A schematic presentation of pathway-dependent and pathway-independent drug resistance mechanisms in cancer cells. In pathway-dependent (black) mechanisms, a possible target receptor becomes activated, either through overexpression or a secondary mutation (for instance, the kinase domain and ectodomain mutation of epidermal growth factor receptor (EGFR) or the overexpression of a truncated version of the target receptor). In addition, gain-of-function mutations in downstream components (e.g., PIK3CA, BRAF, KRAS, etc.) or loss-of-function mutations (PTEN, a well-known inhibitor of the downstream pathway) can proliferate downstream pathways. Other possible pathway-dependent molecular mechanisms include bypass activation, leading to the amplification of other isoforms. Pathway-independent (red) mechanisms generally involve epigenetic changes. The epithelial–mesenchymal transition (EMT) in cancer tissues and the tumor microenvironment plays a vital role in developing resistance against cancer treatment. (M, methylation; dM, demethylation; TKI, tyrosine kinase inhibitors; RTK, receptor tyrosine kinase).

Figure 5

HIF-1α mediates interconnected mechanisms during hypoxia, facilitating chemoresistance in cancer.

Figure 6

Notable nanoparticles that have several applications in the field of medical sciences. (A) Multilamellar liposomes which have several phospholipid bilayer spheres. (B) Large unilamellar liposomes which have single phospholipid bilayer sphere and size of 200 to 800 nm. (C) Small unilamellar liposomes which also have single phospholipid bilayer sphere and size of less than 100 nm. (D) Carbon nanotubes are made of sheets of single-layer carbon atoms. (E) Polymeric nanoparticles which have size ranging from 1 to 1000 nm and also known as colloidal solid particles. (F) Metallic nanoparticles are made of metal as core and organic compound or inorganic metal as sphere. (G) Micelles are composed of amphiphilic macromolecules which range from 5 to 100 nm as nanoparticle. (H) Quantum dots are ultrasmall semiconductor nanoparticle. (I) Dendrimers are nanoparticle organized with core, inner shell and outer shell.