Progress in the studies on the molecular mechanisms associated with multidrug resistance in cancers

Abstract

Chemotherapy is one of the important methods to treat cancer, and the emergence of multidrug resistance (MDR) is one major cause for the failure of cancer chemotherapy. Almost all anti-tumor drugs develop drug resistance over a period of time of application in cancer patients, reducing their effects on killing cancer cells. Chemoresistance can lead to a rapid recurrence of cancers and ultimately patient death. MDR may be induced by multiple mechanisms, which are associated with a complex process of multiple genes, factors, pathways, and multiple steps, and today the MDR-associated mechanisms are largely unknown. In this paper, from the aspects of protein-protein interactions, alternative splicing (AS) in pre-mRNA, non-coding RNA (ncRNA) mediation, genome mutations, variance in cell functions, and influence from the tumor microenvironment, we summarize the molecular mechanisms associated with MDR in cancers. In the end, prospects for the exploration of antitumor drugs that can reverse MDR are briefly discussed from the angle of drug systems with improved targeting properties, biocompatibility, availability, and other advantages.

Keywords: ABC transporter family; Alternative splicing (AS); Gene mutation; Multidrug resistance (MDR); None-coding RNA (ncRNA); Signaling pathway; Tumor microenvironment.

Graphical abstract

Figure 1

Multiple mechanisms associated with MDR in cancers. On the levels of regulatory by anti-tumor drugs, signaling pathways, gene mutations and miRNAs, MDR in cancers could be induced. Clarification of these regulations will unveil potential targets for cancer treatment by combined chemotherapy.

Figure 2

Mechanism for PI3K 110α or 110β subunit to regulate the level of ABC transporters. P110 subunits may regulate ABCB1 and ABCG2, reverse drug-resistance of the cells and change cell proliferation. ABCB1 and ABCG2 were downregulated in the cancer cells in which P110α and P110β subunits were deficient, suggesting the potentiality of P110α and P110β to be applied as targets for reversal of MDR of cancers. This route can be independent of AKT activation. Reproduced with permission from Ref. 4. Copyright ©2020, Springer Nature.

Figure 3

Regulation of CDK6-PI3K axis on MDR in cancer cells. Knockout of cdk6 in KB-C2 with CRISPR/Cas9 technique promoted alternative splicing (AS) in the pre-mRNA expressing ABCB1, generating differential expression level of the transcripts encoding functional ABCB1 protein or truncated abnormal peptides, further decreased the number of functional ABCB1 transporters. With the deficiency of cdk6 in KB-C2 cells, PI3K 110α and 110β expression were downregulated, leading to reversal of ABCB1-mediated MDR, inhibition of cell division as well as promoting cell apoptosis. Meanwhile, a series of signaling pathways associated with malignancies were downregulated in the cdk6-deficient cell population. Reproduced with permission from Ref. . Copyright ©2022 Springer Nature.

Figure 4

As a major effector at the downstream of receptor tyrosine kinase (RTK) and G protein-coupled receptors, the PI3K/AKT pathway is activated by 3′-phosphorylated phosphoinositides and then the activated PI3K/AKT activates various effectors by generating phospholipids, by which signals of various growth factors and cytokines is transduced into intracellular information.

Figure 5

MDR-reversing anti-tumor drugs or drug delivery systems that might be prospective in anti-cancer therapy. In this figure, scheme and structures of the antitumor drugs or combined drug systems that can target MDR cancer cells or tumor microenvironment were illustrated. For the cancer cells, the drugs or drug systems are designed with small sizes (<300 nm in diameter) and can inhibit the ABC proteins directly, or be internalized by the cells, after which they release the active inhibitors or drugs (including plasmid or miRNA) which can induce alteration of the signaling pathways, intracellular homeostasis or autophagy, and consequently MDR in cancer cells is reversed and the cells enters apoptosis. For the tumor microenvironment, the drugs or combined drug systems can be designed with either nano or micro-meter sizes. Functional reagents can be released into the tumor cells to exert activities or remained in the extracellular space to change the extracellular conditions (pH, ROS, O₂, temperature, etc.). Apo: cell apoptosis. TA: targeting ligand. TAA: tumor associated antigen.