Colorectal cancer is the third most commonly occurring cancer worldwide, with an estimated 1.9 million new cases and 930,000 deaths occurring in 2020 globally, accounting for 9.4% of all cancer-related deaths (Morgan et al., 2023). One of the major reasons for poor prognosis and therapy failure in colorectal cancer patients is multidrug resistance (MDR), a phenomenon in which cancer cells develop cross-resistance to anticancer drugs of different structures and pharmacological mechanisms of action (Karthika et al., 2022). Major identified mechanisms of colorectal cancer MDR include drug inactivation, drug target alternation or mutation, aberrated oncogenic or bypass signaling pathways, dysfunctional cell death pathways, and transporters-mediated reduced drug uptake or increased drug efflux (Albadari et al., 2024, Wang et al., 2022). The ATP-binding cassette (ABC) transporters are predominantly involved in drug efflux, which has become a major cause of cancer MDR (Amawi et al., 2019, Bharathiraja et al., 2023). Among the MDR-associated ABC transporters, ABCB1 (P-glycoprotein, P-gp, MDR1) is one of the most common contributors of MDR in colorectal cancer. Tumors that originated from colorectal epithelium gain intrinsic resistance to many widely used chemotherapeutic drugs that are ABCB1 substrates, such as doxorubicin, paclitaxel, and vincristine (To et al., 2020). Moreover, ABCB1 expression is inducible by exposure to chemotherapeutic agents in cancer cells resulting in acquired resistance (Efferth et al., 2020).

A variety of strategies to overcome ABCB1-mediated MDR have been investigated, including the development of drugs with a novel mechanism of action to bypass resistance and the development of novel ABCB1 inhibitors that block efflux and restore drug accumulation when given with anti-cancer drugs (Albadari et al., 2024, Zhang et al., 2021). In particular, the reversal of MDR by ABCB1 modulators has been extensively investigated. Despite showing promising results in laboratory studies, the successful translation of MDR transporter inhibition into clinical applications has been challenging because of undesirable pharmacokinetic profiles or adverse effects (Musyuni et al., 2022, Wang et al., 2019). Therefore, alternative approaches are urgently needed to circumvent or resolve cancer MDR mediated by ABCB1. In the past two decades, the discovery of small molecules that have selective toxicity against ABCB1-expressing cells but not the non-resistant parental cells, a characteristic known as collateral sensitivity (CS), has introduced an alternative strategy to surmount MDR in ABCB1 positive cancer (Efferth et al., 2020, Pluchino et al., 2012, Szakacs et al., 2014). The identification of CS compounds with high selectivity and potency may help prevent MDR when used with chemotherapeutic drugs, or re-sensitize MDR tumors to conventional treatment regimens by selectively killing MDR cells in a heterogeneous tumor population (Pluchino et al., 2012).

The discovery of more CS agents has enhanced our understanding of the mechanism for CS effects against ABCB1-positive cancer, fostering the development of this innovative approach to combat ABCB1-mediated MDR. However, there may be a tremendous difference among the mechanisms of actions by which CS compounds affect ABCB1-dependent biological events. The chemical structure has been thought to be a vital factor in categorizing CS agents of shared action mode (Furedi et al., 2017). The investigation of MDR-selective toxicity through a pharmacogenetic approach has led to the identification of the 8-hydroxyquinoline (8-OHQ) scaffold, notably associated with MDR-selective activity (Szakacs et al., 2004). Several 8-OHQ derivatives, such as NSC693871, NSC693872, and NSC57969, have been identified with increased MDR-selective toxicity (Pape et al., 2022).

Recently, we have discovered MX106 and its analogs, which are designed and synthesized as survivin inhibitors, exhibited potent CS effects killing ABCB1-overexpressing MDR colorectal cancer cells selectively (Xiao et al., 2017). Among those compounds, MX106–4C (5-(((2-bromo-4-methylbenzyl)oxy)methyl)− 7-(pyrrolidine-l-ylmethyl)quinolin-8-ol)) (Fig. 1A) has been identified as a leading compound with the most potent selective toxicity against ABCB1-positive colorectal cancer cells. The core structure of MX106–4C aligns with the pharmacophore of 8-OHQ MDR-selective compounds. The present study aims to investigate the 8-OHQ structure-related mechanisms and the survivin-related on-target mechanisms by which compound MX106–4C selectively kills ABCB1-positive colorectal cancer cells. Furthermore, the efficacy of MX106–4C using co-administrative treatment with anti-cancer drugs or as a re-sensitizing agent in colorectal cancer cells was evaluated.