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    Myeloma Novel Drug Targets and agents

    Category: Myeloma Novel Drug Targets and agents

    Exploiting Silver Nanoparticle (AgNP) Induced Proteotoxicity for Multiple Myeloma Treatment

    (PA-314) Exploiting Silver Nanoparticle (AgNP) Induced Proteotoxicity for Multiple Myeloma Treatment

    Friday, September 19, 2025

    Introduction:      Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by abnormal immunoglobulin overproduction and increased baseline proteotoxicity. Proteasome inhibitors (PIs), like bortezomib (BTZ), are frontline therapies that block protein degradation. This induces toxic protein accumulation, further increasing proteotoxic stress, resulting in MM cell death. Resistance to PIs creates an urgency for more effective therapies. Silver nanoparticles (AgNPs) increase protein oxidation and aggregation to selectively induce cell death in cancers with high protein secretory burden. AgNPs are distinct from silver ions (Ag+), which largely induce oxidative stress. The high baseline levels of proteotoxic stress and reactive oxygen species in MM make it an ideal candidate for AgNP therapy. This study evaluates AgNP-induced cytotoxicity in MM, examining differences between AgNPs and PIs on proteotoxic stress pathways and stromal microenvironment.

    Methods:   AgNP and BTZ IC50 were determined for MM cell lines (JJN3, U266B1, MM1R, and MM1S) and stromal cells (HS5) through cell viability assays. Proteostat staining quantified protein aggregation to confirm induction of proteotoxicity by both therapies. Western blots assessed effects on ubiquitination, heat shock response (HSP70), integrated stress response (p-eif2α and eif2α), and autophagy (LC3-I, LC3-II, and p62) on MM and stromal cells. Stromal and MM cell co-culture experiments evaluated on-target toxicity (MM death) and off-target toxicity (stromal death) of each drug. AgNP and BTZ synergy was determined through fixed-ratio combination dosing; subsequent mono- and co-culture experiments assessed combined treatment efficacy and effects on proteotoxicity.

    Results:   AgNPs and BTZ both induce proteotoxicity through increased protein aggregation, with distinct effects on proteotoxic stress pathways. BTZ treatment resulted in classical indicators of proteotoxicity such as ubiquitinated protein accumulation, increased heat shock response, and integrated stress response activation. AgNPs had little effect on those pathways, with treatment resulting in dysfunctional autophagy. AgNPs alone resulted in less stromal cell death in co-culture at the MM IC50 compared to BTZ. AgNPs and BTZ were highly synergistic in MM cells, with combination treatment at the synergy IC50 resulting in maximal on-target and minimal off-target effects in co-culture. Mechanistically, the combined treatment at the lower doses did not activate indicators of proteotoxicity.  

    Conclusions:   AgNP-induced cytotoxicity effectively treats MM, inducing proteotoxic stress through a distinct mechanism from BTZ. AgNPs and BTZ are highly synergistic, allowing lower drug doses to achieve similar treatment efficacy; the combined mechanism is still unclear. Overall, AgNPs show promise as a second-line therapy for PI-resistant MM as well as a dose-sparing adjunct in frontline PI regimens.