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Zhang et al. Cancer Drug Resist 2024;7:30 https://dx.doi.org/10.20517/cdr.2024.62 Page 7 of 13

The cell cycle encompasses the entirety of processes that a cell undergoes from the conclusion of one
division to the conclusion of the subsequent division, and consists of four consecutive phases: G0/G1 (Gap
[58]
0/1), S (synthesis), G2 (Gap 2), and M (mitosis) . Disruption of the cell cycle is a well-known hallmark of
cancer, and its abnormal activation is associated with drug resistance. Quite a few miRNAs have been found
to regulate genes involved in the cell cycle, leading to drug resistance. Bao et al. found low expression of
[59]
miR-93 in paclitaxel (PTX)-resistant BC samples compared to PTX-responsive patients . This is because
miR-93 inhibits the pRB/E2F1 pathway and AKT phosphorylation by directly targeting E2F1 and CCND1,
which inhibits cell proliferation and cell cycle progression to enhance the therapeutic effect of PTX in vivo.
In addition, E2F1 has been identified as a direct target of miR-302b, which enhances sensitivity to cisplatin
[60]
by regulating the E2F1/ATM axis .

At present, most chemotherapeutic agents induce direct or indirect DNA damage via double-strand breaks
(DSB). DNA damage can be repaired through homologous recombination (HR) or non-homologous
[61]
end-joining (NHEJ) . Enhanced DNA damage repair response (DDRR) will lead to the development of
drug resistance. Therefore, the regulation of DDRR-related genes by miRNA can affect drug sensitivity. Flap
endonuclease 1 (FEN1) participates in various DNA repair pathways. MiR-140 suppresses FEN1 expression
by directly binding to its 3’ untranslated region, which results in impaired DNA repair . The low
[62]
expression of MiR-140 will lead to the resistance of doxorubicin. In addition, miR-30c has been implicated
in adriamycin (ADM) response. MiR-30c targets the DNA repair proteins Fanconi anemia
complementation group F protein (FANCF) and DNA polymerase REV1 (REV1) protein, thereby
[63]
sensitizing the cells to ADM . In p53-mutant BC, mutations in p53 result in decreased miR-30c
expression, leading to ADM resistance.

Cell death is crucial in multiple physiological functions of the human body. Programmed cell death mainly
includes three forms: apoptosis, autophagy, and programmatic necrosis . Since miRNAs and circRNAs can
[64]
regulate cell death, the combination of drugs and miRNAs/circRNAs has been widely studied in anticancer
therapy. It was reported that miR-21-5p can downregulate the expression of programmed cell death 4
[65]
(PDCD4), which leads to paclitaxel resistance . miR-512-3p directly targets the 3’UTR of Livin, which
enhances the antitumor effect of epirubicin, gemcitabine, and docetaxel . In addition, the low expression
[66]
of circ_0006528 can alleviate ADM resistance and reduce the proliferation, migration, and autoplastic
[67]
apoptosis of BC cells . Circ-ABCB10 mediated PTX resistance and apoptosis in BC cells via the let-7a-5p/
DUSP7 axis . Therefore, identifying miRNAs and circRNAs that regulate pro-apoptotic or anti-apoptotic
[68]
proteins to promote apoptosis and reduce resistance to anticancer drugs in cancer cells is a prospective
study.

Another mechanism of chemotherapy resistance involves adenosine triphosphate (ATP)-dependent efflux
pumps that reduce intracellular drug concentrations. ATP binding cassettes (ABCs) are a class of
transmembrane transporters, such as BC resistance protein (BCRP), multidrug resistance-associated protein
[69]
1 (MRP1), and P-glycoprotein (P-gp) . There have been some studies on the regulation of various ABC
transporters in acquired chemotherapy-resistant cells by miRNA and circRNA. MiR-451 can downregulate
[70]
the expression of BCRP, MRP1, and P-gp, thereby reversing the resistance of BC cells to ADM .
Knockdown of circ-CHI3L1.2 downregulated the expression levels of P-GP, MRP1, and glutathione
S-transferase P1 (GSTP1), and impaired cisplatin resistance . Overexpression of P-gp reversed
[71]
circRNA_103615 silencing on cisplatin resistance . In conclusion, exploring the relationship between
[72]
miRNAs/circRNAs, ABC efflux transporter proteins, and anticancer drug resistance is crucial in the search
for new cancer therapeutic targets.