服用 BRAF 抑制剂（例如维莫非尼 (PLX4032)）治疗黑色素瘤的患者中有 20% 至 30% 会发展为皮肤鳞状细胞癌。本研究旨在阐明水薄荷精油的化学预防作用。石灰 (EO) 及其主要成分柠檬烯和香芹酮 (L   C)，占 EO 的 45.68%，可对抗 PLX4032 引起的皮肤副作用。PLX4032 加速皮肤乳头状瘤形成和 7,12-二甲基苯甲醚中角质形成细胞 HRAS 突变[a ]蒽（DMBA）/12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的两阶段皮肤癌小鼠模型用于评估EO和L C的体内生物功效。EO和L的作用和分子机制使用一系列生物活性测定、蛋白质印迹、免疫化学和角质形成细胞-巨噬细胞共培养测定证明了 C 对小鼠 PDVHRASQ61L 角质形成细胞活性的失调。EO 处理抑制了集落形成能力、细胞迁移、侵袭和诱导的 G2/M 细胞- PDVHRASQ61L 角质形成细胞的周期停滞和凋亡，L  C 处理抑制 PDV 细胞的集落形成、细胞迁移和侵袭。在受 DMBA/TPA（DT 组）或 DMBA/TPA 加 PLX4032（DTP 组）刺激的小鼠皮肤中，与 DT 或 DTP 对照相比，局部应用 EO 和 L C 显着延迟了乳头状瘤的出现并降低了乳头状瘤的发生率。组织病理学结果表明，EO 和 L  C 治疗减弱了 K14 角质形成细胞增殖和矛盾的 MAPK 激活，并将小鼠皮肤微环境中的巨噬细胞群从 M2 (CD163 ) 转变为 M1 (iNOS )。 EO或L  C预处理的PDV角质形成细胞的条件培养基促进M0巨噬细胞从THP-1细胞分化为M1样巨噬细胞。这项研究表明，EO和L   C联合使用可预防PLX4032诱导的皮肤副作用和皮肤癌发生通过对小鼠巨噬细胞群进行重新编程并抑制角质形成细胞活性。薄荷 EO 和天然产物 L  C 都可以被认为是有效的化学预防剂，可能有助于减少服用 BRAF 抑制剂的人类患者的皮肤损伤。版权所有 © 2023。由 Elsevier GmbH 出版。

Twenty to thirty percent of patients taking BRAF inhibitors such as vemurafenib (PLX4032) for melanoma develop cutaneous squamous cell carcinomas.This study aimed to elucidate the chemopreventive effect of essential oil from Mentha aquatica L. cv. Lime (EO) and its major constituents, limonene and carvone (L + C) that made up 45.68% of the EO, against PLX4032-induced cutaneous side effects.PLX4032 accelerated skin papilloma formation and keratinocyte HRAS mutation in 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced two-stage skin carcinogenesis mouse model was used to evaluate the in vivo bioefficacy of EO and L + C. The effects and molecular mechanisms of EO and L + C on deregulating mouse PDVHRASQ61L keratinocyte activities were demonstrated using a spectrum of bioactivity assays, western blotting, immunochemistry, and keratinocyte-macrophage co-culture assay.Treatment with EO suppressed colony formation ability, cell migration, invasion, and induced G2/M cell-cycle arrest and apoptosis in PDVHRASQ61L keratinocytes, and L + C treatment inhibited colony formation, cell migration and invasion of PDV cells. In mouse skin irritated with DMBA/TPA (DT group) or DMBA/TPA with PLX4032 (DTP group), topical application of EO and L + C significantly delayed papilloma appearance and reduced papilloma incidence compared to DT or DTP controls. Histopathology results showed that EO and L + C treatment attenuated K14+ keratinocyte proliferation and paradoxical MAPK activation, and shifted the macrophage population from M2 (CD163+) to M1 (iNOS+) in the mouse skin microenvironment. The conditioned medium of EO or L + C pre-treated PDV keratinocytes promoted M0 macrophages to differentiate from THP-1 cells into M1-like macrophages.This study demonstrates that EO and L + C in combination prevent PLX4032-induced cutaneous side-effects and skin carcinogenesis in mice through reprogramming the macrophage cell population and inhibiting keratinocyte activity. Both mint EO and the natural products L + C can be considered to be effective chemopreventive agents that might be useful in reducing cutaneous lesions in human patients administrated with BRAF inhibitors.Copyright © 2023. Published by Elsevier GmbH.