Advances in indole-containing alkaloids as potential anticancer agents by regulating autophagy

Luo, Meng-Lan; Huang, Wei; Zhu, Hongping; Peng, Cheng; Zhao, Qian; Han, Bo

doi:10.1016/j.biopha.2022.112827

Cited by 28 publications

(13 citation statements)

References 124 publications

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“…Accordingly, the potential role of autophagy in cancer is quite complex and has been linked to both the induction and suppression of neoplasia [ 180 , 181 ]. Interestingly, in cancer treatment, diverse indole alkaloids derived from natural sources, such as harmol, chaetoglobosin G, bisleuconothine A, manzamine A, rhynchophylline, and voacamine, have been reported to exert therapeutic effects by targeting autophagy, and the main autophagy-related signaling pathways involve MAPKs pathway, PI3K/Akt/mTOR pathway, JAK2/STAT3 pathway, p62/SQSTM1, Beclin-1, ROS, etc.…”

Section: Targeting Autophagic Signaling Pathways With Indole Alkaloid...mentioning

confidence: 99%

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

et al. 2022

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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

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Section: Targeting Autophagic Signaling Pathways With Indole Alkaloid...mentioning

confidence: 99%

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

et al. 2022

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“…As a result of the C3’ substitution in the spiro core of some inhibitors did not bury inside to MDM2 protein and was directly exposed to the solvent, this position may become appropriate to induce a hydrophobic linker and ZBG to generate HDAC-MDM2 dual inhibitors. As part of our continuing interest in assembling biologically important frameworks as lead compounds for drug discovery ( 73 – 78 ), we herein synthesized a series of spirooxindole-based dual HDAC-MDM2 small-molecule compounds, and evaluated their antitumor activity together with the mechanism of action ( Figure 3C ).…”

Section: Introductionmentioning

confidence: 99%

Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity

et al. 2022

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Simultaneous inhibition of more than one target is considered to be a novel strategy in cancer therapy. Owing to the importance of histone deacetylases (HDACs) and p53-murine double minute 2 (MDM2) interaction in tumor development and their synergistic effects, a series of MDM2/HDAC bifunctional small-molecule inhibitors were rationally designed and synthesized by incorporating an HDAC pharmacophore into spirooxindole skeletons. These compounds exhibited good inhibitory activities against both targets. In particular, compound 11b was demonstrated to be most potent for MDM2 and HDAC, reaching the enzyme inhibition of 68% and 79%, respectively. Compound 11b also showed efficient antiproliferative activity towards MCF-7 cells with better potency than the reference drug SAHA and Nutlin-3. Furthermore, western blot analysis revealed that compound 11b increased the expression of p53 and Ac-H4 in MCF-7 cells in a dose-dependent manner. Our results indicate that dual inhibition of HDAC and MDM2 may provide a novel and efficient strategy for the discovery of antitumor drug in the future.

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“…Indole alkaloids can target cancer autophagy processes, including the MAPK, PI3K/Akt/mTOR, Beclin-1, and ROS signaling pathways. 35…”

Section: Molecular Dockingmentioning

confidence: 99%

Molecular Docking Estrogen Receptor Alpha Antagonist and P53- MDM2 Inhibitor, ADMET Prediction of Alkaloid Compound from Mitragyna speciosa for Breast Cancer Therapy

Priatna¹,

Pratama²,

Widyowati³

et al. 2023

Pharmacogn J.

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Introduction: Breast cancer is one of the major universal health problems affecting more than two million cases per year. Estrogen receptor alpha (ERα) and P53 are common targets for the treatment of breast cancer and are primarily involved in cell proliferation. The function of p53 protein is regulated by direct binding to MDM2 protein. Therefore, inhibition of p53-MDM2 interaction leads to reactivating p53 activity. Alkaloid compounds generally have potential anticancer effect. Alkaloid compound from Mitragyna speciosa have the potential for anticancer. Methods: The method used is molecular docking with AutoDockTools 1.5.6 program. Predict the properties of physicochemical, pharmacokinetic, and toxicity prediction tests (ADMET) using pkCSM. Results: The results showed that speciophylline, corynoxine A, and corynoxine B have the best values in free binding energy (ΔG) for estrogen receptor (ERα) alpha receptor. Meanwhile, mitraphylline, mitrafoline, and corynoxine B have the best values for protein P53. Predict ADMET using the pkCSM, the alkaloid compound has strong lipophilicity and good permeability so it predicts the ability to penetrate intestinal cell membranes and the skin membrane. Spesiofilin, mitraphylline, and mitrafolin are not expected hepatotoxic. Conclusion: Speciophylline and mitraphylline have potential as anticancer drugs through the inhibitory of estrogen receptor alpha and MDM2 reseptor.

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Advances in indole-containing alkaloids as potential anticancer agents by regulating autophagy

Cited by 28 publications

References 124 publications

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

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

Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity

Molecular Docking Estrogen Receptor Alpha Antagonist and P53- MDM2 Inhibitor, ADMET Prediction of Alkaloid Compound from Mitragyna speciosa for Breast Cancer Therapy

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