Comparative analysis of the phototoxicity induced by BRAF inhibitors and alleviation through antioxidants

Abstract

Background Small molecules tackling mutated BRAF (BRAFi) are an important mainstay of targeted therapy in a variety of cancers including melanoma. Albeit commonly reported as side effect, the phototoxic potential of many BRAFi is poorly characterized. In this study, we evaluated the phototoxicity of 17 distinct agents and investigated whether BRAFi‐induced phototoxicity can be alleviated by antioxidants. Methods The ultraviolet (UV) light absorbance of 17 BRAFi was determined. Their phototoxic potential was investigated independently with a reactive oxygen species (ROS) and the 3T3 neutral red uptake (NRU) assay in vitro. To test for a possible phototoxicity alleviation by antioxidants, vitamin C, vitamin E phosphate, trolox, and glutathione (GSH) were added to the 3T3 assay of selected inhibitors. Results The highest cumulative absorbance for both UVA and UVB was detected for vemurafenib. The formation of ROS was more pronounced for all compounds after irradiation with UVA than with UVB. In the 3T3 NRU assay, 8 agents were classified as phototoxic, including vemurafenib, dabrafenib, and encorafenib. There was a significant correlation between the formation of singlet oxygen (P = .026) and superoxide anion (P < .001) and the phototoxicity observed in the 3T3 NRU assay. The phototoxicity of vemurafenib was fully rescued in the 3T3 NRU assay after GSH was added at different concentrations. Conclusion Our study confirms that most of the BRAF inhibitors exhibited a considerable phototoxic potential, predominantly after exposure to UVA. GSH may help treat and prevent the phototoxicity induced by vemurafenib.

Cutaneous Adverse Events of Targeted Therapies and Immune-Checkpoint Inhibitors in Patients with Melanoma

“…Phototoxicity is a common adverse event of vemurafenib (up to 52% of patients) but less frequent with dabrafenib and encorafenib (1%-3%). 4,20,21 Clinically, it presents as an immediate sensation of heat and burning on sun exposure and solar urticaria-like erythema (without pruritus). 5,21 Patients also develop a delayed sunburn-like reaction that can range from mild erythema (Fig.…”

“…21 UVA irradiation of BRAFi produces a UVA-absorbing photoproduct that might be responsible for photosensitivity. 20 Studies also suggest that vemurafenib has an inhibitory effect on UV-induced DNA damage repair. 20 In addition, vemurafenib also inhibits ferrochelatase, resulting in elevated protoporphyrin levels.…”

“…20 Studies also suggest that vemurafenib has an inhibitory effect on UV-induced DNA damage repair. 20 In addition, vemurafenib also inhibits ferrochelatase, resulting in elevated protoporphyrin levels. 21 Before treatment, patients should be instructed about photoprotective measures, including sun-avoidance, protective clothing, and frequent use of broad spectrum sunscreens (UVA and UVB protection).…”

Hymenoptera Toxins: Biological Activity, Pharmaceutical and Therapeutic Uses

“…SK channels have been implicated in diverse physiological functions such as synaptic enhancement and long¬ term potentiation. Apamin injections accelerate acquisition of the bar-pressing response and also accelerate bar-pressing rates [149,150]. Wasp and honey bee and hornet toxin peptides because convulsions due to presence of albumin a rigid octadecapeptide but it is no longer be considered an exclusive neurotoxin.…”

In vitro assessment of the photo(geno)toxicity associated with Lapatinib, a Tyrosine Kinase inhibitor

“…It has been pointed out that the reactive metabolites may be responsible for direct or indirect toxicity to cellular proteins or DNA; however, the underlying mechanisms remain unclear (Parham et al 2016;Spraggs et al 2011). Moreover, it makes sense to investigate the ability of LAP to induce photosensitivity reactions bearing in mind that BRAF (serine/threonine-protein kinase B-Raf) inhibitors show a considerable phototoxic potential after exposure to UVA light (Heppt et al 2020). Besides, it has been reported that afloqualone, a quinazoline-marketed drug, causes photodermatosis as a side effect (Tokura et al 1994).…”