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Review
. 2022 Sep 14;15(1):133.
doi: 10.1186/s13045-022-01350-z.

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

Rui Qin  1 , Feng-Ming You  1 , Qian Zhao  2 , Xin Xie  3 , Cheng Peng  1 , Gu Zhan  4 , Bo Han  5
Affiliations
Review

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

Rui Qin et al. J Hematol Oncol. .

Erratum in

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.

Keywords: Anoikis; Apoptosis; Autophagy; Cancer; Ferroptosis; Indole alkaloids; Mitotic catastrophe; Necroptosis; Regulated cell death (RCD); Target therapy.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Core molecular mechanism of apoptosis, autophagy, ferroptosis, mitotic catastrophe, necroptosis, and anoikis. a There are two well-known signal transduction cascades regulating cell apoptosis: the extrinsic and intrinsic pathways. The extrinsic pathway is activated by death receptors and death ligands, while the intrinsic pathway is initiated by cellular stress-mediated mitochondria dysfunction. b The formation of the autophagosome depends on the formation of a complex incorporating Beclin-1, which is regulated by mTOR. Moreover, various proteins and signaling molecules (AMPK, PI3K, p62, etc.) are involved in the regulation of autophagy. c Ferroptosis is a type of regulated cell death that is induced by the iron-dependent accumulation of lipid reactive oxygen species (ROS) and lipid peroxidation, the inhibition of cystine/glutamate antiporter, and the loss of activity of glutathione peroxidase 4 (GPX4). d The cyclin-dependent kinase 1 (CDK1)/cyclin B1 complex is an important component of mitotic catastrophe and can promote cell cycle transition from G2 phase to M phase. Deoxyribonucleic acid (DNA) damage, mitotic defects, and cytokinesis failure are the three key factors leading to mitotic catastrophes. e Necroptosis is a form of regulated necrotic cell death stimulated by tumor necrosis factor-α (TNF-α). After TNFα binds to the receptor, tumor necrosis factor receptor 1 (TNFR1) recruits TNFRSF1A associated via death domain (TRADD), Fas associated via death domain (FADD), receptor-interacting serine/threonine kinase protein (RIPK) 1, TNF receptor-associated factor 2 (TRAF2) and other proteins to form complex I, and then RIPK1 is deubiquitinated to promote the transformation of complex I to complex II. When caspase-8 is inhibited, mixed lineage kinase domain-like protein (MLKL), RIPK1, and RIPK3 are recruited to form necrosome through phosphorylation, which eventually triggers necroptosis. f Anoikis induces cell death through conventional apoptotic pathways. B cell lymphoma 2 (Bcl-2) related proteins are widely involved in anoikis regulation, and multiple protein kinases are involved in the signal transduction of anoikis. When cells detach from the extracellular matrix (ECM), pro-survival signals cannot be activated, but the death receptors and mitochondrial apoptotic pathways are activated to prevent adherent-independent cell growth and attachment, and finally activate anoikis to induce cell death
Fig. 2
Fig. 2
Classification of indole alkaloids and their representative compounds
Fig. 3
Fig. 3
Representative indole alkaloids in clinical and preclinical studies. A Natural indole alkaloids are an important source of lead compounds, and the above chart shows representative natural indole alkaloids that have been used in clinic. B Indole alkaloids and their derivatives regulate tumor cell apoptosis, autophagy, ferroptosis, mitotic catastrophe, necroptosis, and anoikis, through a variety of cellular signaling pathways, which are currently in preclinical studies and are expected to provide promising strategies for cancer therapy
Fig. 4
Fig. 4
Core apoptosis signaling pathway in cancer. Apoptosis is activated by two pathways, the extrinsic and intrinsic pathways. The extrinsic pathway is triggered by death receptors such as TNFR1, Fas, and death receptor (DR) 4/5 by their related ligands TNF-α, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL). Ligand binding to these receptors leads to the recruitment of FADD and TRADD, and then forms a complex called death-inducing signaling complex (DISC), which in turn results in the cleavage of procaspase-8 and sends a signal to activate caspase-8, thus activating caspase-3, and ultimately leads to apoptosis. The intrinsic pathway is stimulated by cellular stress, leading to p53 and BH3 only proteins activation, which in turn induces Bak/Bax oligomerization and permeabilization of the mitochondria, and ultimately promotes the release of cytochrome C (Cyt-C). Cyt-C forms a complex with apoptotic protease activating factor 1 (Apaf-1) and procaspase-9 and then activates caspase-9. Caspase-9 triggers the caspase-3 activation and induces apoptotic cell death. Besides, the inhibitor of apoptosis protein (IAP) family negatively regulates caspase activation and can be inhibited by second mitochondria-derived activator of caspase (SMAC)/direct IAP-binding protein with low pI (DIABLO), Omi, and apoptosis-related protein in the TGF-β signaling pathway (ARTS). Under certain conditions, cross talk from the extrinsic pathway via caspase-8-mediated truncation of Bid to t-Bid can also cause mitochondrial permeabilization. Additionally, the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) pathways also play essential roles in regulating apoptotic cell death
Fig. 5
Fig. 5
Schematic overview of autophagy. The autophagy process begins with the formation of phagophore structures. The phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway can activate the mammalian target of rapamycin (mTOR) and then regulate the initiation of autophagy through the unc-51-like kinase 1 (ULK1) complex. ULK functions in a complex with autophagy-related genes (ATG) 13, ATG101, and focal adhesion kinase interacting protein of 200 kD (FIP200), and the activation of ULK1 complex occurs through the stimulation of adenosine 5′-monophosphate-activated protein kinase (AMPK) and the suppressing of mTOR. AMPK negatively regulates mTOR, whereas cytoplasmic p53 can activate mTOR by inhibiting AMPK. Autophagy is also modulated by the PI3KCIII interactive complex, which consists of Beclin-1, vacuolar protein sorting 34 (Vps34), Ambra1, and ATG14. The expression of ATG4B, ATG3, and ATG7 converts light chain 3 (LC3) protein from its LC3-I form to LC3-II and promotes autophagosome formation. The combination of mature autophagosome and lysosome leads to autolysosome formation. Ultimately, autolysosomes are degraded by lysosomal hydrolases and recycling nutrients for use in the metabolism
Fig. 6
Fig. 6
Scheme illustrating the effects of brucine-induced ferroptosis in glioma cell
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