Marine Actinomycetes-Derived Secondary Metabolites Overcome TRAIL-Resistance via the Intrinsic Pathway through Downregulation of Survivin and XIAP

Abstract

Resistance of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis represents the major hurdle to the clinical use of TRAIL or its derivatives. The discovery and development of lead compounds able to sensitize tumor cells to TRAIL-induced cell death is thus likely to overcome this limitation. We recently reported that marine actinomycetes’ crude extracts could restore TRAIL sensitivity of the MDA-MB-231 resistant triple negative breast cancer cell line. We demonstrate in this study, that purified secondary metabolites originating from distinct marine actinomycetes (sharkquinone (1), resistomycin (2), undecylprodigiosin (3), butylcyclopentylprodigiosin (4), elloxizanone A (5) and B (6), carboxyexfoliazone (7), and exfoliazone (8)), alone, and in a concentration-dependent manner, induce killing in both MDA-MB-231 and HCT116 cell lines. Combined with TRAIL, these compounds displayed additive to synergistic apoptotic activity in the Jurkat, HCT116 and MDA-MB-231 cell lines. Mechanistically, these secondary metabolites induced and enhanced procaspase-10, -8, -9 and -3 activation leading to an increase in PARP and lamin A/C cleavage. Apoptosis induced by these compounds was blocked by the pan-caspase inhibitor QvD, but not by a deficiency in caspase-8, FADD or TRAIL agonist receptors. Activation of the intrinsic pathway, on the other hand, is likely to explain both their ability to trigger cell death and to restore sensitivity to TRAIL, as it was evidenced that these compounds could induce the downregulation of XIAP and survivin. Our data further highlight that compounds derived from marine sources may lead to novel anti-cancer drug discovery.

Natural Products from Actinobacteria as a Potential Source of New Therapies Against Colorectal Cancer: A Review

“…The chemical structure of these compounds is displayed in Figure 9 . Evident has showed that these compounds are able to reduce the expression of X-linked inhibitor of apoptosis protein (XIAP) and survivin factors, which are members of the inhibitor-of-apoptosis protein (IAP) family recognized for their inhibitory effects on caspase ( Elmallah et al, 2020 ). Thereby they can stimulate the apoptosis of human cancer cells.…”

Targeting Apoptosis to Overcome Chemotherapy Resistance

“…Thymoquinone downregulated the expression of anti-apoptotic proteins and sensitized hepatocarcinoma cells to TRAIL-induced apoptosis (117). Marine actinomycetes-derived secondary metabolites reduced survivin and XIAP proteins and overcame TRAIL resistance in the TNBC cells (118). Skyrin, the active metabolite of Hypericum spp induced DR5 expression and reversed TRAIL resistance in hypoxia and normoxia in the CRC cell lines (119).…”

TRAIL mediated signaling in different cancers: cancer in the "Crosshairs"

“…There is a rapid increase in the identification of natural products having remarkable ability to restore apoptosis in TRAIL-resistant cancers (37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47).…”