methyl-jasmonate and Skin-Neoplasms

Overexpression of hexokinase 2, and its binding to VDAC1 on the outer mitochondrial membrane of cancer cells, is key to their metabolic reprogramming to aerobic glycolysis, which enables them to proliferate. We describe Comp-1, an allosteric small molecule that selectively detaches hexokinase 2 from the mitochondria. Detachment of hexokinase 2 reduces glycolysis and triggers apoptosis in cancer cells, without affecting hexokinase 1-expressing normal cells. The anti-cancer activity of Comp-1 was demonstrated in the UVB-damaged skin model in SKH-1 mice. Topical treatment with Comp-1 led to 70% reduction in lesion number and area. This in vivo efficacy was obtained without local skin reactions or other safety findings. Mechanism-related pharmacodynamic markers, including hexokinase 2 and cleaved caspase 3 levels, are affected by Comp-1 treatment in vivo. Good Laboratory Practice toxicology studies in minipigs for 28 days and 13 weeks established no systemic toxicities and minimal dermal reaction for once-daily application of up to 20% and 15% ointment strengths, respectively. Thus, Comp-1 may address a significant unmet medical need for a non-irritating efficacious topical actinic keratosis treatment.

Topics: Acetates; Animals; Antineoplastic Agents; Apoptosis; Cell Line; Cyclopentanes; Female; Glycolysis; Hexokinase; Humans; Keratosis, Actinic; Mice; Mice, Mutant Strains; Mitochondria; Models, Animal; Neoplasms, Squamous Cell; Oxylipins; Skin; Skin Neoplasms; Swine; Swine, Miniature; Ultraviolet Rays; Voltage-Dependent Anion Channel 1; Xenograft Model Antitumor Assays

Jasmonates are plant stress hormones. These small hydrophobic compounds exhibit anti-cancer activities, in vitro and in vivo, against cancer cells of various histological origins. Moreover, they show a selective activity against transformed cells and affect drug-resistant cells as well.. The aim of this study was to evaluate the activity of a powerful jasmonate derivative, that is methyl jasmonate.. Methyl jasmonate was applied topically on cancerous and pre-cancerous skin lesions from eight patients.. Methyl jasmonate did not cause any meaningful local or systemic side effects. Three patients exhibited positive responses. Two patients had complete recovery and one had a recurrence of the lesion three months post treatment.. Methyl jasmonate is a potentially promising novel topical treatment for prcancerous and cancerous skin lesions. Methyl jasmonate should be evaluated in a larger series of patients.

Topics: Acetates; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Compassionate Use Trials; Cyclopentanes; Female; Humans; Lentigo; Leukoplakia; Lichen Planus, Oral; Male; Middle Aged; Neoplasm Recurrence, Local; Oxylipins; Pilot Projects; Precancerous Conditions; Skin Neoplasms; Time Factors; Treatment Outcome