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  • Verapamil a calcium channel blocker used clinically as

    2019-12-02

    Verapamil, a calcium channel blocker used clinically as a coronary vasodilator, was amongst the first compounds identified that could reverse MDR and potentiate the effects of MDR1 substrates such as vincristine [15], [16]. Verapamil, along with a number of other MDR1 blockers, have proved largely unsuccessful in clinical trials due to toxicity or side effects [17]. Recently, there have been a number of publications reporting that targeted anticancer therapies also reverse MDR by inhibiting the efflux functions of the ABC family of transporters, including ABCB1 (MDR1). Thus the kinase inhibitors imatinib and nilotinib (BCR-Abl inhibitors) [18], gefitinib and erlotinib (EGFR inhibitors) [19], [20], lapatinib (Her-2 inhibitor) [21], apatinib (VEGFR2 inhibitor) [22], and sorafenib (multi-tyrosine and Raf kinases inhibitor) [23] have all been shown to be potent inhibitors of ABCB1. Following observations that the DNA-PK inhibitor NU7441 caused greater sensitisation to cytotoxic agents in MDR1-overexpressing versus non-overexpressing cells, this study aimed to investigate whether NU7441 was interacting with drug efflux via MDR1.
    Materials and methods
    Results
    Discussion It is known that many conventional cytotoxic anticancer drugs are transported out of the cell by MDR1, and it Nicotinic Acid has been shown that MDR1 affects both the intracellular accumulation and intra-tumour distribution of compounds [29]. The importance of the ABC transporter family has been somewhat overlooked in the development of more targeted therapies but a number of recent publications have demonstrated that targeted therapies can interact with this family of transporters [18], [19], [20], [21], [22], [23], [30]. Understanding the role of drug efflux transporters is key when investigating combinations of targeted therapies with drugs that are MDR1 substrates. Inhibition of DNA repair, particularly of double-strand break repair pathways, is an emerging therapeutic strategy in cancer treatment. In the preclinical setting, DNA-PKcs overexpression has been shown in chronic lymphocytic leukaemia patients with del(17p) (associated with p53 mutation) or del(11q) (associated with ATM mutation) chromosomal aberrations and associated with poor prognosis [9]. In addition, enhanced metastasis and poorer prognosis has been observed in patients with lower DNA-PK activity in their peripheral blood lymphocytes [31]. Furthermore, in response to DNA-damaging agents, ATM-defective cells are prevented from undergoing apoptosis and display a strong non-oncogenic addiction to DNA-PKcs [32]. Inhibition of DNA-PK means the ATM-deficient cells cannot repair double-strand breaks and leads to apoptosis and DNA-PK inhibitors have been shown to be an effective monotherapy in ATM-defective lymphomas in vivo [32]. NU7441 is a potent inhibitor of DNA-PK. During investigations of the effect of NU7441 on the activity of a range of chemotherapeutic agents in both parental and multidrug-resistant cells, it was noted that NU7441 sensitised the multidrug-resistant CCRF-CEM VCR/R cells to vincristine, doxorubicin and etoposide and to a greater degree than in parental CCRF-CEM cells. The CCRF-CEM VCR/R cells are resistant to vincristine via overexpression of the efflux transporter MDR1 following stepwise treatment with increasing concentrations of vincristine. Therefore, a potential interaction between NU7441 and MDR1 was hypothesised. Initially, the doxorubicin fluorescence assay demonstrated that NU7441 induces doxorubicin accumulation in a concentration-dependent manner in paired wild-type and MDR1-overexpressing MDCKII cells. The kinase inhibitor sorafenib is used to treat advanced renal cell carcinoma [33] and hepatocellular carcinoma [34], and MDR1 has been shown to play a major role in the acquired resistance phenotype in hepatocellular carcinoma [35]. Furthermore sorafenib has been shown to reverse paclitaxel resistance in MDR cells and cause a concentration-dependent increase in the uptake and retention of rhodamine 123; suggesting that sorafenib inhibits MDR1 [23]. Thus the data with NU7441 are consistent with those for sorafenib.