Periplocin Overcomes Bortezomib Resistance by Suppressing the Growth and Down-Regulation of Cell Adhesion Molecules in Multiple Myeloma

SIMPLE SUMMARY: Multiple myeloma (MM) is a hematologic disorder that is incurable and relapses due to its resistance capability towards bortezomib (BTZ). Our study aimed to overcome the BTZ resistance problem of MM by exploring an anti-MM agent. In this study, we reported the significant inhibition of MM growth upon Periplocin (PP) treatment by using MM wild-type (ARP1) and BTZ-resistant type (ARP1-BR) cell lines. We found the significant induction of apoptosis, inhibition of proliferation, suppression of MM stemness, and reduced cell migration ability of MM by PP treatment. Moreover, cell adhesion molecules (CAMs) were investigated and verified as the molecular targets of PP in MM, which were previously reported as crucial for BTZ resistance in MM. Moreover, PP significantly suppressed the growth of tumors in vivo in the MM irrespective of BTZ resistance. PP is a useful natural anti-MM compound to overcome BTZ resistance and downregulate CAMs in MM. ABSTRACT: Multiple myeloma (MM) is an incurable hematological malignant disorder of bone marrow. Patients with MM receive multiple lines of chemotherapeutic treatments which often develop bortezomib (BTZ) resistance and relapse. Therefore, it is crucial to identify an anti-MM agent to overcome the BTZ resistance of MM. In this study, we screened a library of 2370 compounds against MM wild-type (ARP1) and BTZ-resistant type (ARP1-BR) cell lines and found that periplocin (PP) was the most significant anti-MM natural compound. We further investigated the anti-MM effect of PP by using annexin V assay, clonogenic assays, aldefluor assay, and transwell assay. Furthermore, RNA sequencing (RNA-seq) was performed to predict the molecular effects of PP in MM followed by verification through qRT-PCR and Western blot analysis. Moreover, ARP1 and ARP1-BR xenograft mice models of MM were established to confirm the anti-MM effects of PP invivo. The results showed that PP significantly induced apoptosis, inhibited proliferation, suppressed stemness, and reduced the cell migration of MM. The expression of cell adhesion molecules (CAMs) was suppressed upon PP treatment in vitro and in vivo. Overall, our data recommend PP as an anti-MM natural compound with the potential to overcome BTZ resistance and downregulate CAMs in MM.