Studies on search for bioactive natural products targeting TRAIL signaling leading to tumor cell apoptosis

Ishibashi, Masami; Ohtsuki, Takashi

doi:10.1002/med.20123

Cited by 87 publications

(81 citation statements)

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“…Recent reports show a role of apoptosis in the antineoplastic action of artemisinin and derivatives (11)(12)(13). However, the molecular details of the proapoptotic action of these drugs in tumor cells, particularly the role of the extrinsic and the intrinsic apoptosis pathway, are still controversial (14,15).…”

Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin Induces Apoptosis by a Bak-Dependent Intrinsic Pathway

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Bauer

et al. 2010

Molecular Cancer Therapeutics

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The sesquiterpene lactone dihydroartemisinin (DHA), a semisynthetic derivative of the herbal antimalaria drug artemisinin, is cytotoxic to human tumor cells. Treatment of Jurkat T-lymphoma cells with DHA induced a breakdown of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases, and DNA fragmentation indicative of apoptosis induction. Although the absence of FADD or caspase-8 did not alter apoptosis rates in Jurkat cells, overexpression of dominant-negative caspase-9 or of antiapoptotic Bcl-xL or Bcl-2 largely decreased the cytotoxicity of DHA, demonstrating a role of the intrinsic death pathway. The proapoptotic Bcl-2 effector protein Bak and the Bcl-2 homology domain 3-only protein NOXA turned out to be important mediators of DHA-induced apoptosis in Jurkat cells. DHA treatment triggered the expression of NOXA and the activation of Bak. Furthermore, DHA-induced apoptosis was completely abrogated by loss of Bak and largely reduced in cells with siRNA-mediated downregulation of Bak or NOXA. Proapoptotic signaling of DHA also involved the formation of reactive oxygen species and membrane oxidation. Pretreatment with the lipophilic radical scavenger vitamin E or the hydrophilic radical scavengers glutathione and N-acetylcysteine reduced DHA-induced membrane oxidation and apoptosis, respectively. Oxidative changes also occurred in cells with disruption of the mitochondrial death pathway, suggesting a role of reactive oxygen species and oxidative membrane changes in death signaling upstream of the mitochondria. Interestingly, DHA increased the cytotoxic action of ionizing radiation and of the death receptor agonist tumor necrosis factor-related apoptosis-inducing ligand in Jurkat cells, suggesting a potential benefit of DHA in combined treatment strategies. Mol Cancer Ther; 9(9); 2497-510. ©2010 AACR.

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Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin Induces Apoptosis by a Bak-Dependent Intrinsic Pathway

Handrick

Ontikatze

Bauer

et al. 2010

Molecular Cancer Therapeutics

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“…1 TRAIL-induced apoptosis initiated by the death receptor pathway involves the engagement of death receptors, formation of a deathinducing signaling complex, proteolytic activation of caspase-8 and, consequently, activation of caspase-3. However, considerable numbers of cancer cells are resistant to TRAIL.…”

Section: Introductionmentioning

confidence: 99%

New pyranonaphthoquinones and a phenazine alkaloid isolated from Streptomyces sp. IFM 11307 with TRAIL resistance-overcoming activity

2011

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Four new pyranonaphthoquinones (1-4) were isolated from the liquid culture of Streptomyces sp. IFM 11307. Additionally, one new phenazine derivative (5), along with the known phenazine-1,6-dicarboxylic acid (6) were identified. The chemical structure of compounds 1-6 was elucidated by 1D and 2D NMR spectroscopy together with CD spectral analysis. Compounds 1-4 significantly overcame tumor necrosis factor-related apoptosis-inducing ligand resistance in human gastric adenocarcinoma cell lines.

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“…We herein describe the isolation and structure elucidation of 1 as well as the evaluation of TRAIL resistance-overcoming activity of 1 in human gastric adenocarcinoma (AGS) cell lines as we are interested in screening studies targeting the TRAIL-related cancer selective apoptosis-inducing pathway. 5,6 RESULTS AND DISCUSSION Streptomyces sp. IFM 11307 was cultivated on Waksman medium for 5 days at 28 1C while shaking at 200 r.p.m., and the culture broth (24 l) was centrifuged and then extracted three times with EtOAc.…”

Section: Introductionmentioning

confidence: 99%