A novel plant-derived compound is synergistic with 5-fluorouracil and has increased apoptotic activity through autophagy in the treatment of actinic keratoses

West, Cameron; Kwatra, Shawn G.; Choi, Justin; Hoff, Daniel D. Von; Booth, Laurence; Dent, Paul

doi:10.1080/09546634.2020.1764905

Cited by 12 publications

(49 citation statements)

References 8 publications

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“…We next determined a pathway analysis to determine the mechanisms of cell killing. Prior studies in other cell types have shown GZ17-6.02 killing through mechanisms using the death receptor CD95 and autophagosome formation (10)(11)(12). We also previously demonstrated using other agents that activation of ATM can lead to activation of the AMPK followed by mTOR inactivation, ULK1 activation, ATG13 S318 phosphorylation and autophagosome formation (22).…”

Section: Resultssupporting

confidence: 53%

“…Specific multiple independent siRNAs to knock down the expression of CD95, FADD, Beclin1, ATG5 and eIF2a, and scramble control, were purchased from Qiagen (Hilden Germany). Control studies were presented showing on-target specificity of our siRNAs, primary antibodies and our phosphospecific antibodies to detect both total protein levels and phosphorylated levels of proteins (10)(11)(12)(19)(20)(21)(22)(23)(24).…”

Section: Methodsmentioning

confidence: 99%

“…All bench-side Methods used in this manuscript have been performed and described in the peer-reviewed references (10)(11)(12)(19)(20)(21)(22)(23)(24). All cell lines were cultured at 37°C (5% (v/v CO2) in vitro using RPMI supplemented with dialyzed 5% (v/v) fetal calf serum and 1% (v/v) Non-essential amino acids.…”

Section: Methodsmentioning

confidence: 99%

“…The novel cancer therapeutic GZ17-6.02 undergoing phase I evaluation in solid tumor patients. GZ17-6.02 is comprised of three natural chemicals; curcumin (10%); isovanillin (77%); and harmine (13%) (10)(11)(12). The most widely studied of these three compounds is curcumin; turmeric, the spice most associated with Indian cuisine is comprised~95% of curcumin and curcuminoid derivatives.…”

Section: Introductionmentioning

confidence: 99%

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GZ17-6.02 Interacts With [MEK1/2 and B-RAF Inhibitors] to Kill Melanoma Cells

et al. 2021

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We defined the lethal interaction between the novel therapeutic GZ17-6.02 and the standard of care combination of the MEK1/2 inhibitor trametinib and the B-RAF inhibitor dabrafenib in PDX isolates of cutaneous melanoma expressing a mutant B-RAF V600E protein. GZ17-6.02 interacted with trametinib/dabrafenib in an additive fashion to kill melanoma cells. Regardless of prior vemurafenib resistance, the drugs when combined interacted to prolong ATM S1981/AMPK T172 and eIF2α S51 phosphorylation and prolong the reduced phosphorylation of JAK2 Y1007, STAT3 Y705 and STAT5 Y694. In vemurafenib-resistant cells GZ17-6.02 caused a prolonged reduction in mTORC1 S2448, mTORC2 S2481 and ULK1 S757 phosphorylation; regardless of vemurafenib resistance, GZ17-6.02 caused a prolonged elevation in CD95 and FAS-L expression. Knock down of eIF2α, Beclin1, ATG5, ATM, AMPKα, CD95 or FADD significantly reduced the ability of GZ17-6.02 to kill as a single agent or when combined with the kinase inhibitors. Expression of activated mTOR, activated STAT3, activated MEK1 or activated AKT significantly reduced the ability of GZ17-6.02 to kill as a single agent or when combined with kinase inhibitors; protective effects that were significantly less pronounced in cells treated with trametinib/dabrafenib. Regardless of vemurafenib resistance, the drugs alone or in combination all reduced the expression of PD-L1 and increased the levels of MHCA, which was linked to degradation of multiple HDAC proteins. Our findings support the use of GZ17-6.02 in combination with trametinib/dabrafenib in the treatment of melanomas expressing mutant B-RAF V600E proteins.

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Section: Resultssupporting

confidence: 53%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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GZ17-6.02 Interacts With [MEK1/2 and B-RAF Inhibitors] to Kill Melanoma Cells

et al. 2021

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“…The safe maximal plasma concentration of commercially available lecithin liposomal curcumin, e.g., Meriva ® , for an 800-mg ingestion is approximately 2 µM. Our prior in vitro studies have used GZ17-6.02 with the basal concentration of curcumin set at 2.0 μM ( 1 – 3 ). The plants Arum palaestinum and Peganum harmala have been used for centuries in the Levant and Orient for the treatment of many ailments, including cancer ( 5 – 9 ).…”

Section: Introductionmentioning

confidence: 99%

GZ17-6.02 and Pemetrexed Interact to Kill Osimertinib-Resistant NSCLC Cells That Express Mutant ERBB1 Proteins

et al. 2021

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We determined the molecular mechanisms by which the novel therapeutic GZ17-6.02 killed non-small cell lung cancer (NSCLC) cells. Erlotinib, afatinib, and osimertinib interacted with GZ17-6.02 to kill NSCLC cells expressing mutant EGFR proteins. GZ17-6.02 did not interact with any EGFR inhibitor to kill osimertinib-resistant cells. GZ17-6.02 interacted with the thymidylate synthase inhibitor pemetrexed to kill NSCLC cells expressing mutant ERBB1 proteins or mutant RAS proteins or cells that were resistant to EGFR inhibitors. The drugs interacted to activate ATM, the AMPK, and ULK1 and inactivate mTORC1, mTORC2, ERK1/2, AKT, eIF2α; and c-SRC. Knockdown of ATM or AMPKα1 prevented ULK1 activation. The drugs interacted to cause autophagosome formation followed by flux, which was significantly reduced by knockdown of ATM, AMPKα1, and eIF2α, or by expression of an activated mTOR protein. Knockdown of Beclin1, ATG5, or [BAX + BAK] partially though significantly reduced drug combination lethality as did expression of activated mTOR/AKT/MEK1 or over-expression of BCL-XL. Expression of dominant negative caspase 9 weakly reduced killing. The drug combination reduced the expression of HDAC2 and HDAC3, which correlated with lower PD-L1, IDO1, and ODC levels and increased MHCA expression. Collectively, our data support consideration of combining GZ17-6.02 and pemetrexed in osimertinib-resistant NSCLC.

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