Instructor Houston Methodist Research Institute Houston, Texas, United States
Introduction: Chemotherapy remains the most used systemic treatment for multiple myeloma (MM). However, despite significant improvement in chemotherapy agents, chemoresistance remains the major problem in MM management. Drug resistance has been reported for all clinically used chemotherapy agents, including traditional chemotherapeutics such as melphalan (Mel) and dexamethasone (Dex), and novel agents such as carfilzomib (Cfz). As a result, most, if not all, MM patients experience relapse after treatment and die from the disease. Therefore, overcoming chemoresistance represents a critically unmet clinical need in MM treatment.
Methods: We screened 1855 FDA-approved drugs in human MM cell lines for their ability to sensitize MM cells to chemotherapy drugs. Mechanistic studies were then performed to investigate the target molecules in MM cells and to elucidate the underlying mechanisms.
Results: Our results showed that the selective inhibitors of hepatitis virus replication complex such as EV and DV, an analog of EV, may be used to sensitize and re-sensitize MM cells to chemo-drugs. We found that EV was among the top drugs that significantly sensitized MM cells to Cfz, Dex, and Mel. EV and DV could also re-sensitize Cfz- or Dex-resistant MM cells to Cfz or Dex, respectively. Moreover, in the presence of EV or DV, lower doses of chemo-drugs were required to induce similar MM cell death compared to chemotherapy drugs alone at higher doses. We observed that EV and DV significantly enhanced drug retention in MM cells by inhibiting drug efflux through proteins of ATP-binding cassette (ABC) transporter superfamily. The potential binding proteins were categorized according to their functions. Interestingly, we identified that ATP9B (ATPase phospholipid transporting 9B) and ABCF3 (ATP binding cassette subfamily F member 3), which have transporter activity, in top 20 hits list, were promising targets. We further verified that DV bound to ATP9B and ABCF3 using pull down assay in ARP-1 cells. Depletion of ATP9B or ABCF3 expression sensitized MM cells to chemotherapies. By analyzing published data in Oncomine, ATP9B and ABCF3 were found to be highly expressed in MM cells compared to normal plasma cells, and their expressions in MM cells were negatively associated with treatment outcome in patients. Finally, EV and DV significantly improved the therapeutic efficacy of chemotherapies in MM in vivo without increased toxicity to normal tissues.
Conclusions: These observations strongly suggest that EV and DV, which alone are non-toxic to MM or normal cells have a broad effect in sensitizing MM cells to different chemo-drugs, re-sensitize chemo-refractory MM cells to chemotherapies; and can reduce the doses of chemo-drugs to minimize the side effects of chemotherapy in patients. Our results provide the justification and tools for developing novel and effective strategies for targeting both MM drug efflux to improve the therapeutic efficacy of chemotherapy.