Bisleuconothine A, an eburnane–aspidosperma bisindole alkaloid from Leuconotis griffithii

Hirasawa, Yusuke; Shoji, Tetsuro; Arai, Takashi; Nugroho, Alfarius Eko; Deguchi, Jun; Hosoya, Tsuyoshi; Uchiyama, Nahoko; Goda, Yukihiro; Awang, Khalijah; Hadi, A. Hamid A.; Shiro, Motoo; Morita, Hiroshi

doi:10.1016/j.bmcl.2010.01.051

Cited by 34 publications

(30 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, we identified bisindole alkaloids as Wnt signaling inhibitor by using a cell-based luciferase assay system, among which, Bisleuconothine A (BLA) showed the most potent activity. Bisleuconothine A, a bisindole with an eburnane-aspidosperma skeleton firstly reported from the bark of Leuconotis griffithii , exhibited cell growth inhibitory activity against various human cancer cell lines [ 23 ]. We showed that Bisleuconothine A, as a novel and selective Wnt signaling inhibitor, had great potential to be further developed as colorectal cancer therapeutics targeting the Wnt signaling.…”

Section: Introductionmentioning

confidence: 99%

Bisleuconothine A, a bisindole alkaloid, inhibits colorectal cancer cell in vitro and in vivo targeting Wnt signaling

et al. 2016

View full text Add to dashboard Cite

Wnt signaling pathway is aberrantly activated in a variety of cancers, especially in colorectal cancer and small molecule antagonists of Wnt/β-catenin signaling are attractive candidates for developing effective therapeutics. In the present study, we identified Bisleuconothine A, a bisindole alkaloid with an eburnane-aspidosperma type skeleton, as a novel and selective Wnt signaling inhibitor by using a cell-based luciferase assay system. Our study found that Bisleuconothine A down-regulated the endogenous Wnt target gene expression through promoting phosphorylation of β-catenin and the subsequent inhibition of its nuclear translocation in HCT116 and SW480 colorectal cancer cells. In vitro, Bisleuconothine A inhibited cell proliferation through induction of apoptosis by increasing the cleavage of caspases in HCT116 and SW480 colorectal cancer cells. Moreover, in vivo, Bisleuconothine A dramatically suppressed tumor growth in HCT116 Xenograft. And further analysis showed that Bisleuconothine A suppressed the Wnt target gene expression in HCT116 Xenograft, which was associated with up-regulation of β-catenin phosphorylation and subsequent Wnt signaling inhibition. Taken together, our study indicated that bisindole alkaloids could be included as a new chemotype of small-molecule Wnt signaling inhibitors, and have great potential to be further developed for anti-tumor agents.

show abstract

Section: Introductionmentioning

confidence: 99%

Bisleuconothine A, a bisindole alkaloid, inhibits colorectal cancer cell in vitro and in vivo targeting Wnt signaling

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The IC 50 value of Bis-A was determined at approximately 8 μM (IC 50 value of previous article was at 6 μM). 17 Furthermore, no significant cell death was observed microscopically (data not shown), suggesting Bis-A to have cytostatic activity. However, treatment of Bis-A at higher concentration (24 μM) for 48 h slightly increased cell death, as confirmed from microscopic observations.…”

Section: ■ Results and Discussionmentioning

confidence: 89%

Bisleuconothine A Induces Autophagosome Formation by Interfering with AKT-mTOR Signaling Pathway

et al. 2015

Self Cite

View full text Add to dashboard Cite

We have previously reported that bisleuconothine A (Bis-A), a novel bisindole alkaloid isolated from Leuconotis griffithii, showed cytostatic activity in several cell lines. In this report, the mechanism of Bis-A-induced cytostatic activity was investigated in detail using A549 cells. Bis-A did not cause apoptosis, as indicated by analysis of annexin V and propidium iodide staining. Expression of all tested apoptosis-related proteins was also unaffected by Bis-A treatment. Bis-A was found to increase LC3 lipidation in MCF7 cells as well as A549 cells, suggesting that Bis-A cytostatic activity may be due to induction of autophagy. Subsequent investigation via Western blotting and immunofluorescence staining indicated that Bis-A induced formation but prevented degradation of autophagosomes. Mechanistic studies showed that Bis-A down-regulated phosphorylation of protein kinase B (AKT) and its downstream kinase, PRAS40, which is an mTOR repressor. Moreover, phosphorylation of p70S6K, an mTOR-dependent kinase, was also down-regulated. Down-regulation of these kinases suggests that the increase in LC3 lipidation may be due to mTOR deactivation. Thus, the cytostatic activity shown by Bis-A may be attributed to its induction of autophagosome formation. The Bis-A-induced autophagosome formation was suggested to be caused by its interference with the AKT-mTOR signaling pathway.

show abstract

“…[77] The SAR indicated that the introduction of either electron-donating or electron-withdrawing group into the C-2 and/or C-5 position of indole moiety was detrimental to the activity. Titanocene T (39) induced a moderate to good reduction in tumor growth compared with the control group without causing apparent toxicity in the mice model. [78] The bisindole-pyrrolo and arrest sub-G1 phase as well.…”

Section: Bisindole Hybridsmentioning

confidence: 89%

“…[37] The mechanistic study indicated that this bisindole alkaloid could induce G1 phase arrest and cellular apoptosis through A549 cancer cell lines. [38,39] The mechanistic study indicated that bisleuconothine A could inhibit cell proliferation through the induction of apoptosis by increasing the cleavage of caspases in HCT116 and SW480 colorectal cancer cells. [40] In the HCT116…”

Section: Bisindole Alkaloidsmentioning

confidence: 99%

Anticancer activity of bisindole alkaloids derived from natural sources and synthetic bisindole hybrids

Zhang

2020

Archiv der Pharmazie

View full text Add to dashboard Cite

The bisindole moiety, as a versatile pharmacophore, is one of the widespread heterocycles in naturally occurring and synthetic bioactive compounds. The bisindole alkaloids derived from natural sources possess structural and mechanistic diversity, and they were found to be generally more active than monoindole alkaloids against various cancer cell lines. Moreover, some bisindole alkaloids such as the tubulin inhibitors, vinorelbine and vinblastine, have already been approved for cancer therapy, suggesting that bisindole alkaloids are a significant source of anticancer agents and lead hits. Bisindole hybrids have the potential to overcome drug resistance, enhance efficiency, and reduce severe side effects. The bisindole–lactam hybrid midostaurin has already been approved for the treatment of adult patients with newly diagnosed acute myeloid leukemia who are FLT3 mutation‐positive, highlighting the importance of bisindole hybrids in the development of novel anticancer agents. In this review, we present a brief account of the bisindole alkaloids derived from nature and of synthetic hybrids with potential anticancer activity developed in the recent 10 years.

show abstract

Bisleuconothine A, an eburnane–aspidosperma bisindole alkaloid from Leuconotis griffithii

Cited by 34 publications

References 9 publications

Bisleuconothine A, a bisindole alkaloid, inhibits colorectal cancer cell in vitro and in vivo targeting Wnt signaling

Bisleuconothine A, a bisindole alkaloid, inhibits colorectal cancer cell in vitro and in vivo targeting Wnt signaling

Bisleuconothine A Induces Autophagosome Formation by Interfering with AKT-mTOR Signaling Pathway

Anticancer activity of bisindole alkaloids derived from natural sources and synthetic bisindole hybrids

Contact Info

Product

Resources

About