GZ17-6.02 With Proteasome Inhibitors Kills Multiple Myeloma Cells

“We believe that developing GZ17-6.02 as a novel multiple myeloma agent potentially opens up a multitude of novel opportunities to develop therapeutic approaches which will prolong patient survival.”

BUFFALO, NY- March 6, 2024 – A new research paper was published in Oncotarget's Volume 15 on March 5, 2024, entitled, “GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells.”

In this new study, researchers Laurence Booth, Jane L. Roberts, Cameron West, and Paul Dent from Virginia Commonwealth University and Genzada Pharmaceuticals investigated GZ17-6.02, a synthetically manufactured compound containing isovanillin, harmine and curcumin, in multiple myeloma cells. GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525) with a recommended phase 2 dose (RP2D) of 375 mg PO BID. GZ17-6.02 was more efficacious as a single agent at killing multiple myeloma cells than had previously been observed in solid tumor cell types.

"GZ17-6.02 interacted with proteasome inhibitors in a greater than additive fashion to kill myeloma cells and alone it killed inhibitor-resistant cells to a similar extent."

The drug combination of GZ17-6.02 and bortezomib activated ATM, the AMPK and PERK and inactivated ULK1, mTORC1, eIF2α, NFκB and the Hippo pathway. The combination increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM, and reduced the levels of BCL-XL and MCL1. GZ17-6.02 interacted with bortezomib to enhance autophagosome formation and autophagic flux, and knock down of ATM, AMPKα, ULK1, Beclin1 or ATG5 significantly reduced both autophagy and tumor cell killing. Knock down of BAK and BIM significantly reduced tumor cell killing. 

The expression of HDACs1/2/3 was significantly reduced beyond that previously observed in solid tumor cells and required autophagy. This was associated with increased acetylation and methylation of histone H3. Combined knock down of HDACs1/2/3 caused activation of ATM and the AMPK and caused inactivation of ULK1, mTORC1, NFκB and the Hippo pathway. HDAC knock down also enhanced ATG13 phosphorylation, increased BAK levels and reduced those of BCL-XL. 

“Collectively, our present studies support performing additional in vivo studies with multiple myeloma cells.”

Read the full paper: DOI: https://doi.org/10.18632/oncotarget.28558 

Correspondence to: Paul Dent

Email: paul.dent@vcuhealth.org 

Keywords: autophagy, ER stress, GZ17-6.02, bortezomib, proteasome inhibitor

Click here to sign up for free Altmetric alerts about this article.

About Oncotarget: Oncotarget (a primarily oncology-focused, peer-reviewed, open-access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

To learn more about Oncotarget, visit Oncotarget.com and connect with us on social media:

X, formerly Twitter
Facebook
YouTube
Instagram
LinkedIn
Pinterest
Spotify, and available wherever you listen to podcasts

Click here to subscribe to Oncotarget publication updates.

For media inquiries, please contact media@impactjournals.com.

Oncotarget Journal Office

6666 East Quaker Str., Suite 1A

Orchard Park, NY 14127

Phone: 1-800-922-0957 (option 2)