Ultrasound-Potentiated Targeting of GLS1 by an Oridonin Derivative (R13) in Multiple Myeloma: Therapeutic Efficacy and Safety Considerations

Abstract

Objective:

To create a structurally optimized oridonin derivative (R13) and study its safety profile, molecular mechanism, and ultrasound-enhanced antitumor activity in multiple myeloma (MM), with an emphasis on glutamine metabolism-driven oncogenic signaling.

Materials and Methods:

Using oridonin as the parent nucleus, photocatalytic double-bond addition and esterification processes were used to create R13. Using CCK-8, colony formation, and Transwell assays, the antiproliferative, anticlonogenic, and anti-invasive effects of R13 were assessed in MM cell lines (U266 and KMS-11) both on its own and in response to low-intensity ultrasonic exposure. Key elements of the glutaminase 1–protein kinase B (GLS1-AKT) signaling axis were evaluated for modification using quantitative reverse transcription-polymerase chain reaction (RT-PCR). Stable cell lines with GLS1 knockdown and overexpression were created to confirm target reliance and ultrasound-mediated sensitization. To assess systemic toxicity, organ safety, and in vivo antitumor activity under combination treatment settings, a nude mouse xenograft model was created.

Results:

In a dose- and time-dependent way, R13 dramatically reduced MM cell proliferation, and colony formation, invasion, and migration; these effects were further enhanced by exposure to ultrasound. Mechanistically, R13 specifically targeted and downregulated GLS1, leading to inhibition of the GLS1-AKT signaling pathway, which is characterized by overexpression of the tumor suppressor PTEN and lower expression of AKT2, AKT3, and GSK-3β without changing the expression of AKT1. The biological benefits of R13 and its ultrasound-enhanced pathway regulation were partially reversed by GLS1 overexpression, indicating GLS1-dependent therapeutic action. R13 therapy significantly slowed the growth of xenograft tumors in vivo, while coadministration with ultrasound increased the anticancer activity. Major organs showed no discernible histopathological damage, suggesting a good safety profile.

Conclusions:

Through ultrasound-potentiated suppression of GLS1-driven metabolic and AKT signaling pathways, R13, a new oridonin derivative, exhibits strong anti-MM action with little systemic toxicity. These results support the combination of drugs originating from Traditional Chinese Medicine with noninvasive ultrasound techniques to enhance treatment efficacy while preserving safety, and they show R13 as a good option for ultrasound-augmented biotherapy in MM.