HSP70 inhibition reverses cell adhesion mediated and acquired drug resistance in multiple myeloma

Area of Science:

• Molecular Biology
• Oncology
• Cell Biology

Background:

• Heat shock proteins (HSPs) are crucial molecular chaperones induced by cellular stress.
• HSP70 is known to inhibit chemotherapy-induced apoptosis.
• Multiple myeloma (MM) cells can develop drug resistance upon adhesion to stromal cells.

Purpose of the Study:

• To investigate the role of HSP70 in chemoresistance of multiple myeloma (MM) cells.
• To determine if HSP70 mediates cell adhesion-associated drug resistance (CAM-DR) in MM.

Main Methods:

• Utilized MM cell lines and primary plasma cells.
• Assessed HSP70 expression following cell adhesion to bone marrow stromal cells or fibronectin (FN).
• Employed HSP70 inhibitors and a heat shock factor inhibitor (KNK-437) to evaluate effects on cell adhesion, apoptosis, and drug resistance.

Main Results:

• MM cell adhesion to stroma or FN enhanced HSP70 expression.
• HSP70 inhibition decreased MM cell adhesion and increased apoptosis in FN-adhered cells.
• HSP70 inhibitors reversed melphalan-induced CAM-DR and enhanced melphalan-induced apoptosis.
• KNK-437 induced apoptosis in melphalan-resistant MM cells and primary CD138+ cells.

Conclusions:

• HSP70 plays a significant role in mediating chemoresistance in multiple myeloma.
• Inhibiting HSP70 reduces MM cell adhesion and overcomes both acquired and de novo drug resistance.
• Targeting HSP70 presents a promising therapeutic strategy for overcoming drug resistance in MM.