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

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.

N6-methyladenosine-modified circ_0000337 sustains bortezomib resistance in multiple myeloma by regulating DNA repair

“…However, bortezomib resistance often occurs in the course of use, which affects the therapeutic effect of MM (Liu et al, 2021). Although several mechanisms of bortezomib resistance have been reported, mainly related to genetic alterations in multiple myeloma, the exact cause remains unknown (Chroma et al, 2022;Aziz et al, 2023;Ochiai et al, 2023). Therefore, it is imperative to decipher the underlying molecular mechanisms of bortezomib resistance and to explore new strategies to counteract it.…”