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[Display omitted] • 11 type-A withanolides including 4 new ones, were isolated from the dietary tomatillo. • Physalin F was found to be a new inhibitor of mutant IDH1. • Its inhibitory activity was confirmed by mutant IDH1 and cell-based experiments. • Tomatillo could be used as potential antitumor functional food or drug. Isocitrate dehydrogenase (IDH) is one key rate-limiting enzyme in the tricarboxylic acid cycle, which is related to various cancers. Tomatillo (Physalis ixocarpa), a special tomato, is widely consumed as nutritious vegetable in Mexico, USA, etc. As a rich source for withanolides, the fruits of P. ixocarpa were investigated, leading to the isolation of 11 type-A withanolides including 4 new ones (1 is an artificial withanolide). All these withanolides were evaluated for their inhibition on mutant IDH1 enzyme activity. Among them, physalin F (11) exhibited potent enzyme inhibitory activity and binding affinity with mutant IDH1. It inhibits the proliferation of HT1080 cells by selectively inhibiting the activity of mutant IDH1. Since Ixocarpalactone A, another major type-B withanolide in this plant, could act on another energy metabolism target PHGDH, the presence of different types of withanolides in tomatillo and their synergistic effect could make it a potential antitumor functional food or drug. [ABSTRACT FROM AUTHOR]

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare disorder that leads to painful blisters and large open wounds of the skin that do not heal. Individuals with RDEB often develop skin tumours called cutaneous squamous cell carcinoma (cSCC), which are difficult to treat and rapidly get worse. The overall risk of death in patients with RDEB and cSCC can be up to 90% by the age of 55 years due to disease complications. We and others have found that patients with RDEB and related cSCC have increased levels of a protein called transforming growth factor‐beta (TGF‐β). This protein controls processes (signals) within cells that can affect cell growth and development. TGF‐β signalling is known to have a dual role in tumour development by either increasing or blocking cancer cell growth. The aim of this study, carried out by researchers from the UK, the USA and Mexico, was to clarify whether increased levels of TGF‐β promote or inhibit growth of cSCC in patients with RDEB. This is important to assess for these patients because it could improve treatment options, which are significantly lacking for these patients To assess whether targeting TGF‐β signalling is a possible treatment option, we used cells extracted from patients with RDEB and cSCC and showed that drugs that block TGF‐β in cancer cells could help the majority of these patients, specifically those where TGF‐β is contributing to tumour cell growth. However, we also found that in a small number of patients, TGF‐β slows down tumour growth, and therefore using drugs to block TGF‐β might be harmful for this patient group. Based on our findings, studies such as clinical trials using drugs targeting TGF‐β should be done cautiously due to the possibility of these drugs actually causing harm in some patients with RDEB and cSCC. This research highlights the different roles of TGF‐β in RDEB skin cancer, and therefore the need to identify those patients who might benefit from using drugs targeting TGF‐β signalling. Linked Article: Dayal et al. Br J Dermatol 2021; 184:697–708. Linked Article: Dayal et al. Br J Dermatol 2021; 184:697–708. [ABSTRACT FROM AUTHOR]