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A Novel Microtubule-Disrupting Agent Induces Endoplasmic Reticular Stress-Mediated Cell Death in Human Hepatocellular Carcinoma Cells.

ABSTRACT: Here, we present evidence of a novel microtubule-disrupting agent, N-deacetyl-N-(chromone-2-carbonyl)-thiocolchicine (TCD), exhibiting potent antitumor activity (with IC50 values in the nanomolar range) against hepatocellular carcinoma cell lines. Cell cycle analysis revealed that TCD induced G2/M cell-cycle arrest in a dose- and time-dependent manner in both Hep-J5 and Mahlavu HCC cell lines. TCD also induced a decrease in mitochondrial membrane potential (??m) and caused DNA damage. Mechanistically, TCD activated protein kinase RNA-like endoplasmic reticular kinase and several transcription factors, including activating transcription factor (ATF) 6, ATF4, ATF3, and the CCAAT-enhancer binding protein homologous protein. These data clearly demonstrate that the antitumor activity of TCD is mechanistically linked to its capacity to trigger both intrinsic and extrinsic apoptotic cell death via endoplasmic reticular stress pathway. The potent antitumor activity of TCD was similarly demonstrated in a hepatocellular carcinoma xenograft model, where 5 and 10 mg/kg doses of TCD significantly arrested Hep-J5 and Mahlavu tumor growth. Our finding suggests that TCD is a promising therapeutic agent against hepatocellular carcinoma; further translational assessment of its clinical usage is warranted.

SUBMITTER: Ho CT

PROVIDER: S-EPMC4565632 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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A Novel Microtubule-Disrupting Agent Induces Endoplasmic Reticular Stress-Mediated Cell Death in Human Hepatocellular Carcinoma Cells.

Ho Chun-Te CT Chang Yu-Jia YJ Yang Li-Xi LX Wei Po-Li PL Liu Tsan-Zon TZ Liu Jun-Jen JJ

PloS one 20150910 9

Here, we present evidence of a novel microtubule-disrupting agent, N-deacetyl-N-(chromone-2-carbonyl)-thiocolchicine (TCD), exhibiting potent antitumor activity (with IC50 values in the nanomolar range) against hepatocellular carcinoma cell lines. Cell cycle analysis revealed that TCD induced G2/M cell-cycle arrest in a dose- and time-dependent manner in both Hep-J5 and Mahlavu HCC cell lines. TCD also induced a decrease in mitochondrial membrane potential (ΔΨm) and caused DNA damage. Mechanisti ...[more]

PMID: 26355599

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Project description:Liver cancers, such as hepatocellular carcinoma (HCC), are a highly prevalent cause of cancer-related deaths. Current treatments to combat liver cancer are limited. (-)-Agelasidine A, a compound isolated from the methanol extract of Agelasnakamurai, a sesquiterpene guanidine derived from sea sponge, has antibacterial activity. We demonstrated its anticancer capabilities by researching the associated mechanism of (-)-agelasidine A in human liver cancer cells. We found that (-)-agelasidine A significantly reduced viability in Hep3B and HepG2 cells, and we determined that apoptosis was involved in the (-)-agelasidine A-induced Hep3B cell deaths. (-)-Agelasidine A activated caspases 9, 8, and 3, as well as PARP. This effect was reversed by caspase inhibitors, suggesting caspase-mediated apoptosis in the (-)-agelasidine A-treated Hep3B cells. Moreover, the reduced mitochondrial membrane potential (MMP) and the release of cytochrome c indicated that the (-)-agelasidine A-mediated mitochondrial apoptosis was mechanistic. (-)-Agelasidine A also increased apoptosis-associated proteins (DR4, DR5, FAS), which are related to extrinsic pathways. These events were accompanied by an increase in Bim and Bax, proteins that promote apoptosis, and a decrease in the antiapoptotic protein, Bcl-2. Furthermore, our results presented that (-)-agelasidine A treatment bridged the intrinsic and extrinsic apoptotic pathways. Western blot analysis of Hep3B cells treated with (-)-agelasidine A showed that endoplasmic reticulum (ER) stress-related proteins (GRP78, phosphorylated PERK, phosphorylated eIF2α, ATF4, truncated ATF6, and CHOP) were upregulated. Moreover, 4-PBA, an ER stress inhibitor, could also abrogate (-)-agelasidine A-induced cell viability reduction, annexin V+ apoptosis, death receptor (DR4, DR5, FAS) expression, mitochondrial dysfunction, and cytochrome c release. In conclusion, by activating ER stress, (-)-agelasidine A induced the extrinsic and intrinsic apoptotic pathways of human HCC.

Project description:Several biological effects of haem oxygenase (HO)-1, including anti-inflammatory, antiapoptotic and antioxidative properties were reported; however, the role of HO-1 in apoptosis is still unclear. In the presence of stimulation by cobalt protoporphyrin (CoPP), an HO-1 inducer, apoptotic characteristics were observed, including DNA laddering, hypodiploid cells, and cleavages of caspase (Casp)-3 and poly(ADP) ribose polymerase (PARP) proteins in human colon carcinoma COLO205, HCT-15, LOVO and HT-29 cells in serum-free (SF) conditions with increased HO-1, but not heat shock protein 70 (HSP70) or HSP90. The addition of 10% foetal bovine serum (FBS) or 1% bovine serum albumin accordingly inhibited CoPP-induced apoptosis and HO-1 protein expression in human colon cancer cells. CoPP-induced apoptosis of colon cancer cells was prevented by the addition of the pan-caspase inhibitor, Z-VAD-FMK (VAD), and the Casp-3 inhibitor, Z-DEVD-FMK (DEVD). N-Acetyl cysteine inhibited reactive oxygen species-generated H2 O2 -induced cell death with reduced intracellular peroxide production, but did not affect CoPP-induced apoptosis in human colorectal carcinoma (CRC) cells. Two CoPP analogs, ferric protoporphyrin and tin protoporphyrin, did not affect the viability of human CRC cells or HO-1 expression by those cells, and knockdown of HO-1 protein expression by HO-1 small interfering (si)RNA reversed the cytotoxic effect elicited by CoPP. Furthermore, the carbon monoxide (CO) donor, CORM, but not FeSO4 or biliverdin, induced DNA ladders, and cleavage of Casp-3 and PARP proteins in human CRC cells. Increased phosphorylated levels of the endoplasmic reticular (ER) stress proteins, protein kinase R-like ER kinase (PERK), and eukaryotic initiation factor 2α (eIF2α) by CORM and CoPP were identified, and the addition of the PERK inhibitor, GSK2606414, inhibited CORM- and CoPP-induced apoptosis. Increased GRP78 level and formation of the HO-1/GRP78 complex were detected in CORM- and CoPP-treated human CRC cells. A pro-apoptotic role of HO-1 against the viability of human CRC cells via induction of CO and ER stress was firstly demonstrated herein.

Dataset Information

A Novel Microtubule-Disrupting Agent Induces Endoplasmic Reticular Stress-Mediated Cell Death in Human Hepatocellular Carcinoma Cells.

Publications

A Novel Microtubule-Disrupting Agent Induces Endoplasmic Reticular Stress-Mediated Cell Death in Human Hepatocellular Carcinoma Cells.

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