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GZ17-6.02 interacts with bexarotene to kill mycosis fungoides cells
Michael R Booth1, Laurence Booth1, Jane L Roberts1
1Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
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.
Insights
GZ17-6.02 effectively kills mycosis fungoides (MF) cells by activating multiple cell death pathways, including ER stress and autophagy. All three components of GZ17-6.02 are crucial for its potent anti-cancer activity in MF.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Mycosis fungoides (MF) is a type of cutaneous T-cell lymphoma with limited treatment options.
- The anti-cancer effects of GZ17-6.02, a combination of curcumin, harmine, and isovanillin, have not been previously investigated in MF cells.
Purpose of the Study:
- To elucidate the biological mechanisms underlying the efficacy of GZ17-6.02 in malignant T cells from MF patients.
- To determine the role of individual components and signaling pathways in GZ17-6.02-mediated cell death.
Main Methods:
- In vitro studies using MF cell lines.
- Analysis of key signaling pathways (ATM, AMPK, NFκB, PERK, ERK1/2, AKT, mTORC1, eIF2α).
- Assessment of autophagy markers (ATG13, Beclin1, ATG5), apoptosis regulators (BCL-XL, MCL1, BAK, BIM), and cell death mediators (CD95, AIF, caspase 3).
- Investigation of GZ17-6.02's impact on autophagosome formation and autophagic flux.
Main Results:
- GZ17-6.02 demonstrated potent killing of MF cells, both alone and in combination with standard therapies.
- All three components of GZ17-6.02 were essential for optimal tumor cell killing.
- GZ17-6.02 modulated multiple signaling pathways, including activation of ATM, AMPK, NFκB, and PERK, and inactivation of ERK1/2, AKT, ULK1, mTORC1, and eIF2α.
- The drug enhanced autophagosome formation and autophagic flux in a dose-dependent manner.
- ATM and AMPK signaling were required for efficient killing, while ER stress and macroautophagy were critical for both killing and dose-response.
- CD95, AIF, and caspase 3 played significant roles in GZ17-6.02-induced cell death.
Conclusions:
- GZ17-6.02 is a multi-factorial agent that induces cell death in MF cells through a combination of ER stress, macroautophagy, death receptor signaling, and mitochondrial dysfunction.
- The study provides a mechanistic basis for the anti-cancer activity of GZ17-6.02 in MF and suggests its potential as a therapeutic agent.
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