A plant sesquiterpene lactone and its derivative reduce cutaneous side effect of vemurafenib,a BRAF inhibitor drug to treat late stage melanoma

OBJECTIVE To investigate the pharmacological effect of a plant sesquiterpene lactone(designated D)and its semi-organically synthesized novel derivative(designated S)and the role of lipid mediators,viz.,oxylipins in attenuating vemurafenib-induced cutaneous side effects.METHODS A DMBA/TPAinduced skin carcinogenesis mouse model mimicking cutaneous side effect caused by vemurafenib was established to evaluate the efficacy of compound D and S in reversal of vemurafenib side effect.Comparative oxylipin metabolomics platform using UPLC-TQD mass spectrometry coupled with partial least squares-discriminant analysis(PLS-DA)analysis,cell-based assays,and immunochemistry analysis were performed to elucidate the mechanism insights of DET and S compounds and the role of specific oxylipins in skin cancer carcinogenesis.RESULTS Vemurafenib treatment expedited the skin papillomas formation in DMBA-TPA treated mouse from week 6 to week 3.Both D and S compounds could suppress the vemurafenib side effect and also decrease total papillomas numbers(55% to 72%)and average sizes(66% to 89%).Oxylipins metabolome analysis shows that specific arachidonic acid metabolites may play a role in vemurafenib-induced squamous cell carcinoma or keratoacanthomas formation in mouse skin that can be deregulated by D or S compound treatment.Notably,S compound can inhibit vemurafenib-induced paradoxical activation of MAP kinases in mouse skin or in NRAS mutant melanoma cells.CONCLUSION Our results indicate that plant sesquiterpene lactone D and its novel analog can reduce cutaneous side effect of vemurafenib through novel modes of action by inhibiting paradoxical activation of MAP kinases and de-regulating pro-inflammation mediators COX-2 and specific ecosanoid-type of oxylipins.This study may suggest a novel adjuvant therapy approach in treatment of BRAFV600 Emutant melanoma.