CHM-1 induces apoptosis via p38-mediated upregulation of DR5 expression in human ovarian cancer SKOV3 cells

Lee, Jang Chang; Chou, Li Chen; Huang, Chih Chia; Chung, Jing Gung; Huang, Li Jiau; Lee, Kuo Hsiung̀; Hung, Mien Chie; Way, Tzong‐Der; Kuo, Sheng Chu

doi:10.1016/j.ejphar.2011.08.006

Cited by 17 publications

(10 citation statements)

References 34 publications

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“…However, DR5 can also be regulated in a cell type-specific, trigger-dependent, and p53-independent manner, but the underlying mechanisms remain largely unclear [53,54]. Our data showed p53 was not associated with DR5 upregulation in ChK-treated OVCAR-3 and A2780/CP70 cells, which was in agreement with the previous study conducted in human ovarian cancer SKOV3 cells induced by CHM-1 [55]. This result indicated that p53-dependent pathway might not be the unique mechanism of apoptosis induced by ChK in OVCAR-3 and A2780/ CP70 cells.…”

Section: Discussionsupporting

confidence: 92%

Chaetoglobosin K induces apoptosis and G2 cell cycle arrest through p53-dependent pathway in cisplatin-resistant ovarian cancer cells

Gao

Rankin

et al. 2015

Cancer Letters

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Adverse side effects and acquired resistance to conventional platinum based chemotherapy have become major impediments in ovarian cancer treatment, and drive the development of more selective anticancer drugs. Chaetoglobosin K (ChK) was shown to have a more potent growth inhibitory effect than cisplatin on two cisplatin-resistant ovarian cancer cell lines, OVCAR-3 and A2780/CP70, and was less cytotoxic to a normal ovarian cell line, IOSE-364, than to the cancer cell lines. Hoechst 33342 staining and Flow cytometry analysis indicated that ChK induced preferential apoptosis and G2 cell cycle arrest in both ovarian cancer cells with respect to the normal ovarian cells. ChK induced apoptosis through a p53-dependent caspase-8 activation extrinsic pathway, and caused G2 cell cycle arrest via cyclin B1 by increasing p53 expression and p38 phosphorylation in OVCAR-3 and A2780/CP70 cells. DR5 and p21 might play an important role in determining the sensitivity of normal and malignant ovarian cells to ChK. Based on these results, ChK would be a potential compound for treating platinum-resistant ovarian cancer.

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Section: Discussionsupporting

confidence: 92%

Chaetoglobosin K induces apoptosis and G2 cell cycle arrest through p53-dependent pathway in cisplatin-resistant ovarian cancer cells

Gao

Rankin

et al. 2015

Cancer Letters

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“…As mitogen-activated protein kinases (MAPKs), including the extracellular signal-regulated kinases (ERKs), JNKs and p38-MAPKs, can mediate DR5 upregulation, 18, 27, 28 we first investigated whether these kinases had a role in CK-induced DR5 expression. The results showed that CK increased JNK phosphorylation, but decreased ERK or p38 phosphorylation, in a dose-dependent manner (Figure 5a).…”

Section: Resultsmentioning

confidence: 99%

Ginsenoside compound K sensitizes human colon cancer cells to TRAIL-induced apoptosis via autophagy-dependent and -independent DR5 upregulation

et al. 2016

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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell-specific apoptosis-inducing cytokine with little toxicity to most normal cells. However, acquired resistance of cancer cells to TRAIL is a roadblock. Agents that can either potentiate the effect of TRAIL or overcome resistance to TRAIL are urgently needed. This article reports that ginsenoside compound K (CK) potentiates TRAIL-induced apoptosis in HCT116 colon cancer cells and sensitizes TRAIL-resistant colon cancer HT-29 cells to TRAIL. On a cellular mechanistic level, CK downregulated cell survival proteins including Mcl-1, Bcl-2, surviving, X-linked inhibitor of apoptosis protein and Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein, upregulated cell pro-apoptotic proteins including Bax, tBid and cytochrome c, and induced the cell surface expression of TRAIL death receptor DR5. Reduction of DR5 levels by siRNAs significantly decreases CK- and TRAIL-mediated apoptosis. Importantly, our results indicate, for the first time, that DR5 upregulation is mediated by autophagy, as blockade of CK-induced autophagy by 3-MA, LY294002 or Atg7 siRNAs substantially decreases DR5 upregulation and reduces the synergistic effect. Furthermore, CK-stimulated autophagy is mediated by the reactive oxygen species–c-Jun NH2-terminal kinase pathway. Moreover, we found that p53 and the C/EBP homologous (CHOP) protein is also required for DR5 upregulation but not related with autophagy. Our findings contribute significantly to the understanding of the mechanism accounted for the synergistic anticancer activity of CK and TRAIL, and showed a novel mechanism related with DR5 upregulation.

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“…The extrinsic pathway is initiated by ligation of transmembrane death receptors (Fas, DR4/5 and TNFR1) with their respective ligands (FasL, TRAIL and TNFα) triggering the for-mation of a death-inducing complex to active caspase-8, which in turn cleaves and activates caspase-3 (Ashkenazi and Dixit, 1998;Thorburn, 2004). Enhanced TRAIL expression and stimulation of DR4-and/or DR5-induced apoptosis has been shown in certain types of cancers, including colon, ovarian, prostate, bladder and chronic lymphocytic leukaemia (O'Flaherty et al, 2006;Lee et al, 2011;Thomas et al, 2013). In the present study, we found that 11e treatment up-regulated the expression of the DR5 protein and influenced the expression of TRAIL (Figure 12).…”

Section: Figure 11mentioning

confidence: 99%

Synthesis and SAR studies of novel 6,7,8‐substituted 4‐substituted benzyloxyquinolin‐2(1H)‐one derivatives for anticancer activity

Chen

Lin

Morris‐Natschke³

et al. 2015

British J Pharmacology

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Background and Purpose 4‐Phenylquinolin‐2(1H)‐one (4‐PQ) derivatives can induce cancer cell apoptosis. Additional new 4‐PQ analogs were investigated as more effective, less toxic antitumour agents. Experimental Approach Forty‐five 6,7,8‐substituted 4‐substituted benzyloxyquinolin‐2(1H)‐one derivatives were synthesized. Antiproliferative activities were evaluated using a 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazoliun bromide assay and structure–activity relationship correlations were established. Compounds 9b, 9c, 9e and 11e were also evaluated against the National Cancer Institute‐60 human cancer cell line panel. Hoechst 33258 and Annexin V‐FITC/PI staining assays were used to detect apoptosis, while inhibition of microtubule polymerization was assayed by fluorescence microscopy. Effects on the cell cycle were assessed by flow cytometry and on apoptosis‐related proteins (active caspase‐3, ‐8 and ‐9, procaspase‐3, ‐8, ‐9, PARP, Bid, Bcl‐xL and Bcl‐2) by Western blotting. Key Results Nine 6,7,8‐substituted 4‐substituted benzyloxyquinolin‐2(1H)‐one derivatives (7e, 8e, 9b, 9c, 9e, 10c, 10e, 11c and 11e) displayed high potency against HL‐60, Hep3B, H460, and COLO 205 cancer cells (IC50 < 1 μM) without affecting Detroit 551 normal human cells (IC50 > 50 μM). Particularly, compound 11e exhibited nanomolar potency against COLO 205 cancer cells. Mechanistic studies indicated that compound 11e disrupted microtubule assembly and induced G2/M arrest, polyploidy and apoptosis via the intrinsic and extrinsic signalling pathways. Activation of JNK could play a role in TRAIL‐induced COLO 205 apoptosis. Conclusion and Implications New quinolone derivatives were identified as potential pro‐apoptotic agents. Compound 11e could be a promising lead compound for future antitumour agent development.

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CHM-1 induces apoptosis via p38-mediated upregulation of DR5 expression in human ovarian cancer SKOV3 cells

Cited by 17 publications

References 34 publications

Chaetoglobosin K induces apoptosis and G2 cell cycle arrest through p53-dependent pathway in cisplatin-resistant ovarian cancer cells

Chaetoglobosin K induces apoptosis and G2 cell cycle arrest through p53-dependent pathway in cisplatin-resistant ovarian cancer cells

Ginsenoside compound K sensitizes human colon cancer cells to TRAIL-induced apoptosis via autophagy-dependent and -independent DR5 upregulation

Synthesis and SAR studies of novel 6,7,8‐substituted 4‐substituted benzyloxyquinolin‐2(1H)‐one derivatives for anticancer activity

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