Combinations of ivermectin with proteasome inhibitors induce synergistic lethality in multiple myeloma

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Multiple myeloma (MM) is a fatal plasma cell malignancy with limited treatment options.
• Ivermectin, an antiparasitic drug, has potential anticancer properties that warrant investigation.
• Proteasome inhibitors are a cornerstone of MM therapy, but resistance can develop.

Purpose of the Study:

• To investigate the anti-MM effects of ivermectin, both as a single agent and in combination with proteasome inhibitors.
• To elucidate the molecular mechanisms underlying ivermectin's activity against MM cells.
• To evaluate the therapeutic potential of ivermectin in preclinical MM models.

Main Methods:

• In vitro studies assessed ivermectin's effects on MM cell viability, proteasome activity, and cellular pathways.
• Mechanism of action studies involved evaluating proteasome subunit nuclear import and downstream signaling.
• In vivo efficacy was tested using a human MM xenograft mouse model treated with ivermectin and bortezomib.

Main Results:

• Ivermectin demonstrated mild anti-MM activity in vitro by inhibiting nuclear proteasome import and inducing protein ubiquitination and UPR activation.
• Ivermectin treatment led to DNA damage and activated the DNA damage response pathway in MM cells.
• Combination therapy with ivermectin and bortezomib showed synergistic anti-MM effects, enhanced proteasome inhibition, and increased DNA damage in vitro and in vivo, with good tolerability.

Conclusions:

• Ivermectin exhibits significant anti-multiple myeloma activity by targeting proteasome function and inducing DNA damage.
• Ivermectin synergizes with bortezomib, suggesting a potential combination therapy for MM.
• Ivermectin represents a promising therapeutic agent for multiple myeloma treatment, either alone or in combination regimens.