Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets

Abstract

Regulated cell death (RCD) is a critical and active process that is controlled by specific signal transduction pathways and can be regulated by genetic signals or drug interventions. Meanwhile, RCD is closely related to the occurrence and therapy of multiple human cancers. Generally, RCD subroutines are the key signals of tumorigenesis, which are contributed to our better understanding of cancer pathogenesis and therapeutics. Indole alkaloids derived from natural sources are well defined for their outstanding biological and pharmacological properties, like vincristine, vinblastine, staurosporine, indirubin, and 3,3′-diindolylmethane, which are currently used in the clinic or under clinical assessment. Moreover, such compounds play a significant role in discovering novel anticancer agents. Thus, here we systemically summarized recent advances in indole alkaloids as anticancer agents by targeting different RCD subroutines, including the classical apoptosis and autophagic cell death signaling pathways as well as the crucial signaling pathways of other RCD subroutines, such as ferroptosis, mitotic catastrophe, necroptosis, and anoikis, in cancer. Moreover, we further discussed the cross talk between different RCD subroutines mediated by indole alkaloids and the combined strategies of multiple agents (e.g., 3,10-dibromofascaplysin combined with olaparib) to exhibit therapeutic potential against various cancers by regulating RCD subroutines. In short, the information provided in this review on the regulation of cell death by indole alkaloids against different targets is expected to be beneficial for the design of novel molecules with greater targeting and biological properties, thereby facilitating the development of new strategies for cancer therapy. Graphic abstract

Callyspongia spp.: Secondary Metabolites, Pharmacological Activities, and Mechanisms

“…The alkaloid that has been identified from ethanolic extract of Callyspongia siphonella was 5-bromo trisindoline and 6-bromo trisindoline [ 7 ]. Although the specific mechanism of 5-bromo trisindoline and 6-bromo trisindoline is unknown, some indole alkaloids were known to interfere with the nuclear factor-κB and c-Jun N-terminal kinase signaling pathways [ 90 , 91 ], preventing the synthesis or action of specific pro-inflammatory cytokines, and suppressing histamine release and nitric oxide production ( Figure 7 ) [ 92 , 93 ]. Alkaloids are effective for treating inflammatory bowel disease [ 94 , 95 , 96 , 97 ].…”

Exploring the effectiveness of Chinese herbal medicine as an "iron blade" to get rid of a "hidden murderer" hypertension

“…TP53 inactivation or mutation is one of the most frequent occurrences in human malignancies [41]. When TP53 binds to the SLC7A11 gene promoter region, it transcriptionally represses the gene's expression to cause ferroptosis in the human osteosarcoma cell line U2OS and the human breast cancer cell line MCF7 [42]. The subunit of the heterodimeric transcription factor HIF1, HIF1A, plays a crucial part in the transcriptional response to variations in oxygen availability implicated in metabolism, immunity, migration, and survival [43].…”

Correction: Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets

“…The original article [ 1 ] mistakenly omitted co-corresponding authorship of co-author, Gu Zhan. This has since been restored.…”