Multidrug resistance (MDR) is a term used to describe the resistance of cancer cells to multiple chemotherapeutic drugs, which have distinctly different structures and mechanisms of action (Wang et al., 2021a). This resistance can arise either from inherent properties of cancer cells or from acquiring resistance during chemotherapy, ultimately leading to treatment refractoriness, tumor recurrence, and increased mortality (Wang et al., 2021a, Horsey et al., 2016). Among the primary mechanisms contributing to MDR, ATP-binding cassette (ABC) transporters’ overexpression plays a pivotal role (Wang et al., 2021a, Chun et al., 2015). The ABC transporter superfamily encompasses 49 members (Kumar et al., 2012), including ABCB1 [P-glycoprotein (P-gp), multidrug resistance 1 (MDR1) protein], ABCG2 [breast cancer resistance protein (BCRP), mitoxantrone resistance (MXR)], ABCC1 [multidrug resistance-associated protein 1 (MRP1)], and ABCC10 [multidrug resistance protein 7 (MRP7)] (Wang et al., 2021a). These transporter proteins function as efflux pumps, facilitating the extrusion of anticancer drugs from cancer cells (Chun et al., 2015). The ABCG2 transporter is usually overexpressed in breast, ovarian, lung, gastric, and colon cancer (Wang et al., 2021a). Moreover, much evidence has shown that the ABCC1 transporter also leads to resistance of cancer cells (Wang et al., 2021a). Most current strategies aimed at overcoming MDR involve the development of reversal agents that can inhibit or deactivate ABC transporters, thereby increasing intracellular concentrations of anticancer drugs (Wang et al., 2021a, Li et al., 2017).

Poly (ADP-ribose) polymerase (PARP) is a family of proteins that play a crucial role in detecting and transmitting signals related to DNA damage (Brownlie et al., 2023, Tang et al., 2023). PARPs participate in diverse DNA repair processes, including genome integrity maintenance, DNA methylation, apoptosis induction, programmed cell death, transcriptional regulation, and metabolic control. Using synthetic lethality to exploit deficiencies in the DNA repair pathway, PARP inhibitors have recently emerged as a targeted therapy for cancer (Brownlie et al., 2023). Rucaparib, olaparib, niraparib, and talazoparib (BMN-673) are examples of PARP inhibitors that can interact with the NAD+ binding site within the catalytic domain of PARP, thereby inhibiting DNA repair activity (Tang et al., 2023, Valabrega et al., 2021, Almeida et al., 2017, Boussios et al., 2020). Talazoparib was the most potent PARP inhibitor, and it could capture PARP1 about one hundred times more efficiently than niraparib (Cortesi et al., 2021). It elicits antitumor responses and triggers DNA repair markers at significantly lower concentrations than earlier-generation PARP1/2 inhibitors (Oza et al., 2017, Penson et al., 2019, Moore et al., 2019). Talazoparib is generally well-tolerated, widely distributed in tissues, possesses favorable pharmacokinetics, and exhibits excellent oral bioavailability (Oza et al., 2017, Penson et al., 2019). In comparison to other PARP inhibitors, talazoparib demonstrates enhanced stereospecific PARP-DNA capture ability, augmenting the cytotoxic effects of temozolomide, carboplatin, and the active metabolites of irinotecan (SN-38) (Cortesi et al., 2021, Murai et al., 2014, Pommier et al., 2016). The side effects associated with talazoparib more closely resemble those of traditional chemotherapy drugs as opposed to other clinically approved PARP inhibitors (Boussios et al., 2020).

Ovarian cancer ranks among the most prevalent malignant tumors affecting the female reproductive system (Siegel et al., 2019). The primary approach to treating ovarian cancer involves surgical cytoreduction followed by platinum-based chemotherapy (Torre et al., 2018). Exciting advancements have been made in using PARP inhibitors to combat ovarian cancer (Skorda et al., 2022). Although only 15-20% of ovarian cancer cases exhibit germline or somatic mutations in BRCA1 or BRCA2, approximately 30-50% display deficiencies in homologous recombination (HR) DNA repair (Ragupathi et al., 2023, Moon et al., 2023, Lau et al., 2022). HR-deficient cells heavily rely on alternative DNA repair pathways for survival, presenting a potential vulnerability to DNA-damaging agents (Alhmoud et al., 2020). PARP is vital in identifying DNA single-strand breaks (SSBs) and orchestrating DNA repair through HR-dependent mechanisms (Ray Chaudhuri and Nussenzweig, 2017). In HR-deficient cancer cells, blocking PARP activity results in the accumulation of DNA double-strand breaks (DSBs) and subsequent cell death (Ray Chaudhuri and Nussenzweig, 2017, Wang et al., 2021b). The advent of PARP inhibitors has revolutionized the treatment landscape for ovarian cancer patients (Bahena-González et al., 2020, Musella et al., 2018), with the inclusion of a PARP inhibitor in chemotherapy regimens now serving as a primary therapeutic approach for treating both BRCA-mutated ovarian cancer (Hong et al., 2021) and advanced ovarian cancer with HR deficiencies (Konecny and Kristeleit, 2016, Moore et al., 2018).

The relationship between PARP inhibitors and drug efflux transporters, particularly ABC transporters, plays a crucial role in understanding resistance mechanisms. Increased drug efflux, where compounds like PARP inhibitors are rapidly removed from cells, has been linked to PARP inhibitors resistance. Research indicated that olaparib-resistant breast cancers exhibit increased expression of ABCB1, ranging from a 2- to 85-fold increase (Rottenberg et al., 2008). This overexpression was also correlated with resistance to olaparib and rucaparib in ovarian cancer cell lines. Encouragingly, the resistance was effectively reversed by the administration of ABCB1 inhibitors like verapamil or elacridar, as demonstrated by Vaidyanathan et al (Vaidyanathan et al., 2016). in 2016. It is worth noting that ABCB1 overexpression did not induce resistance to veliparib or AZD2461, an analog of olaparib. This observation suggests that while ABCB1 gene expression contributes to PARP inhibitor resistance, it may not be the sole underlying mechanism, highlighting the complexity of resistance development in response to PARP inhibitors.

PARP inhibitors represent a breakthrough in treating ovarian and other types of cancer with defects in DNA repair pathways. However, the development of drug resistance poses a significant challenge to their clinical application. This study investigates the impact of ABCC1 and ABCG2 on the resistance to talazoparib, a potent PARP inhibitor, in ovarian cancer treatment.