Oncotarget

Research Papers:

GZ17-6.02 interacts with bexarotene to kill mycosis fungoides cells

Michael R. Booth, Laurence Booth, Jane L. Roberts, Cameron West and Paul Dent _

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Oncotarget. 2024; 15:124-133. https://doi.org/10.18632/oncotarget.28557

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Abstract

Michael R. Booth1, Laurence Booth1, Jane L. Roberts1, Cameron West2 and Paul Dent1

1 Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA

2 Genzada Pharmaceuticals, Hutchinson, KS 67502, USA

Correspondence to:

Paul Dent, email: [email protected]

Keywords: autophagy; ER stress; GZ17-6.02; bexarotene; vorinostat

Received: December 01, 2023     Accepted: January 23, 2024     Published: February 08, 2024

Copyright: © 2024 Booth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

GZ17-6.02, composed of curcumin, harmine and isovanillin, has undergone phase I evaluation in patients with solid tumors (NCT03775525) with an RP2D of 375 mg PO BID. The biology of GZ17-6.02 in malignant T cells and in particular those derived from mycosis fungoides (MF) patients, has not been studied. GZ17-6.02 alone and in combination with standard-of-care agents was effective in killing MF cells. All three components are necessary for optimal killing of MF cells. GZ17-6.02 activated ATM, the AMPK, NFκB and PERK and inactivated ERK1/2, AKT, ULK1, mTORC1, eIF2α, and reduced the expression of BCL-XL and MCL1. GZ17-6.02 increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM. GZ17-6.02 in a dose-dependent fashion enhanced autophagosome formation and autophagic flux, and tumor cell killing. Signaling by ATM and AMPK were both required for efficient killing but not for the dose-response effect whereas ER stress (eIF2α) and macroautophagy (Beclin1, ATG5) were required for both efficient killing and the dose-response. Knock down of the death receptor CD95 reduced killing by ~20% and interacted with autophagy inhibition to further reduce killing, collectively, by ~70%. Inhibition of autophagy and knock down of death-mediators downstream of the mitochondrion, AIF and caspase 3, almost abolished tumor cell killing. Hence in MF cells, GZ17-6.02 is a multi-factorial killer, utilizing ER stress, macroautophagy, death receptor signaling and directly causing mitochondrial dysfunction.


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