Maraviroc enhances Bortezomib sensitivity in multiple myeloma by inhibiting M2 macrophage polarization via PI3K/AKT/RhoA signaling pathway in macrophages

Background: Multiple myeloma (MM) is a malignancy where drug resistance often leads to relapse or refractory disease. Chemokine Receptor 5 (CCR5) has emerged as a novel therapeutic target. However, the role of CCR5-antagonist Maraviroc (MVC) in M2 macrophage polarization and its potential to enhance Bortezomib sensitivity in MM has not been fully explored.

Methods: We used human bone marrow samples, RPMI 8226 cells, and THP-1 monocytes to investigate CCL3/CCR5 axis. ELISA measured CCL3/CCR5 levels. Knockdown/overexpression vectors modulated expression. Cell proliferation, Apoptosis, and macrophage polarization were assessed using CCK8, flow cytometry, and transwell assays. QRT-PCR analyzed CCL3 expression, and western blotting examined PI3K/Akt/RhoA signaling. CCR5 was targeted via siRNAs or MVC. NOD/SCID mouse model evaluated CCL3/CCR5 effects on macrophage polarization and MVC's impact on Bortezomib efficacy.

Results: CCL3, CCR5, and M2 macrophage markers are upregulated in MM patients, with CCL3/CCR5 expression correlating with M2 macrophage polarization. Myeloma-secreted CCL3 and paracrine CCR5 significantly promoted M2 macrophage polarization by activating PI3K/Akt/RhoA signaling, which in turn enhanced myeloma proliferation, inhibited Apoptosis, and reduced Bortezomib sensitivity. MVC inhibited M2 macrophage polarization and improved Bortezomib sensitivity in vitro and xenograft mouse myeloma models.

Conclusions: MVC reduced macrophage polarization and enhanced Bortezomib sensitivity in MM cells.

CCL3/CCR5; M2 polarization; Multiple myeloma; PI3K/AKT/RhoA; Tumor microenvironment.