A number of prostate cancer (PCa)‐specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor olaparib used as single agent for treatment of metastatic castration‐resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa, we evaluated a potential use for olaparib in combination with first‐line endocrine treatments, androgen deprivation, and complete androgen blockade, and as a maintenance therapy following on from endocrine therapy. We demonstrate that the LNCaP cell line, possessing multiple aberrations in BRCAness genes, is sensitive to olaparib. Additive effects of olaparib combined with endocrine treatments in LNCaP are noted. In contrast, we find that the TMPRSS2:ERG fusion‐positive cell lines VCaP and DuCaP do not show signs of synthetic lethality, but are sensitive to cytotoxic effects caused by olaparib. In consequence, additive effects of olaparib with endocrine therapy were not observable in these cell lines, showing the need for synthetic lethality in combination treatment regimens. Additionally, we show that PCa cells remain sensitive to olaparib treatment after initial androgen deprivation implicating a possible use of olaparib as maintenance therapy. In sum, our preclinical data recommend olaparib as a synthetic lethal treatment option in combination or sequenced to first‐line endocrine therapy for PCa patients with diagnosed BRCAness.
Inflammatory skin diseases, including atopic dermatitis (AD) and psoriasis, are increasing in populations worldwide. The treatment of patients with AD and other forms of skin inflammation is mainly based on the use of topical corticosteroids or calcineurin inhibitors, which can cause significant side effects with long-term use. Therefore, there is a great need for the development of more effective and less toxic anti-inflammatory agents suitable for the treatment of chronic skin lesions. Here, we screened a number of strains from the ASIB 505 terrestrial algae collection and identified a green algae Chromochloris zofingiensis with pronounced anti-inflammatory properties. We found that a crude nonpolar extract of C. zofingiensis (ID name NAE_2022C), grown upon nitrogen deprivation, acts as a bioactive substance by inhibiting TNFR/NF-κB responses in human skin keratinocyte HaCaT cells. We also found that NAE_2022C suppressed the secretion of pro-inflammatory cytokine tumor necrosis factor α (TNFα) and several Th1- and Th2-related chemokines in a reconstituted human epidermis. The TNFR/NF-κB pathway analysis showed multiple inhibitory effects at different levels and disclosed a direct targeting of IKKβ by the extract. Bioassay-guided fractionation followed by high-resolution mass spectrometry detected diacylglyceryl-trimethylhomoserine (DGTS), Lyso-DGTS (LDGTS), 5-phenylvaleric acid, theophylline and oleamide as leading metabolites in the active fraction of NAE_2022C. Further analysis identified betaine lipid DGTS (32:0) as one of the active compounds responsible for the NAE_2022C-mediated NF-κB suppression. Overall, this study presents an approach for the isolation, screening, and identification of anti-inflammatory secondary metabolites produced by soil algae.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.