ChemInform Abstract: Synthesis and Identification of Novel Indolo[2,3‐a]pyrimido[5,4‐c]carbazoles as a New Class of Anticancer Agents.

Pierce, Larry T.; Cahill, Michael G.; Winfield, Hannah; McCarthy, Florence O.

doi:10.1002/chin.201313152

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“…In 1986, this compound was found to be a non-specific nanomolar inhibitor of PKC in vitro and was regarded as a new platform for the design of potent, non-toxic, and selective antiproliferative agents [11,12] . Bisindolylmaleimides, a series of derivative compounds, have received considerable attention in clinical trials, and they exhibit potential as anti-cancer drugs [13] .…”

Section: Original Articlementioning

confidence: 99%

Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway

Sun

et al. 2017

Acta Pharmacol Sin

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Bisindolylmaleimides, a series of derivatives of a PKC inhibitor staurosporine, exhibit potential as anti-cancer drugs and have received considerable attention in clinical trials. This study aims to investigate the effects of a bisindolylmaleimide alkaloid 155Cl (BMA-155Cl) with a novel structure on autophagy and apoptosis in human hepatocarcinoma HepG-2 cells in vitro and in vivo. The cell poliferation was assessed with a MTT assay. Autophagy was evaluated by MDC staining and TEM analysis. Apoptosis was investigated using Annexin V-FITC/PI and DAPI staining. The antitumor effects were further evaluated in nude mice bearing HepG-2 xenografts, which received BMA-155Cl (10, 20 mg/kg, ip) for 18 days. Autophagy-and apoptosis-associated proteins and their mRNA levels were examined with Western blotting, immunohistochemistry, and RT-PCR. BMA-155Cl (2.5-20 μmol/L) inhibited the growth of HepG-2 cells with IC 50 values of 16.62±1.34, 12.21±0.83, and 8.44±1.82 μmol/L at 24, 48, and 72 h, respectively. Furthermore, BMA155Cl (5-20 μmol/L) dose-dependently induced autophagy and apoptosis in HepG-2 cells. The formation of autophagic vacuoles was induced by BMA-155Cl (10 μmol/L) at approximately 6 h and peaked at approximately 15 h. Pretreatment with 3-MA potentiated BMA-155Cl-mediated apoptotic cell death. This compound dose-dependently increased the mRNA and protein levels of Beclin-1, NF-κB p65, p53, and Bax, but decreased the expression of IκB and Bcl-2. Pretreatment with BAY 11-7082, a specific inhibitor of NF-κB p65, blocked BMA-155Cl-induced expression of autophagy-and apoptosis-associated proteins. BMA-155Cl administration effectively suppressed the growth of HepG-2 xenografts in vivo, and increased the protein expression levels of LC3B, Beclin-1, NF-κB p65, and Bax in vivo. We conclude that the NF-κB p65 pathway is involved in BMA-155Cl-triggered autophagy, followed by apoptosis in HepG-2 cells in vitro and in vivo. Hence, BMA-155Cl could be a promising pro-apoptotic candidate for developing as a novel anti-cancer drug.

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Section: Original Articlementioning

confidence: 99%

Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway

Sun

et al. 2017

Acta Pharmacol Sin

View full text Add to dashboard Cite

show abstract

ChemInform Abstract: Synthesis and Identification of Novel Indolo[2,3‐a]pyrimido[5,4‐c]carbazoles as a New Class of Anticancer Agents.

Cited by 1 publication

References 1 publication

Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway

Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway

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