Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes

Qiao, Li; Yacoub, Adly; Studer, Elaine; Gupta, Seema; Pei, Xin Yan; Grant, Steven; Hylemon, Philip B.; Dent, Paul

doi:10.1053/jhep.2002.32533

Cited by 132 publications

(109 citation statements)

References 46 publications

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“…45,46 Pro-apoptotic activity of UDCA was also demonstrated in hepatocytes. 47 Although the mechanisms driving tumor suppressive activity are not fully understood yet, the tumor suppressive activity of UDCA is explained by its potential to activate pro-apoptotic mechanisms, inhibit the cell cycle, or prevent oncogenic factors. In addition, the anti-inflammatory action of UDCA has been suggested to be a crucial mechanism underlying treatment of various disorders, including cancer, primary sclerosing cholangitis and inflammation in symptomatic gallbladders with cholesterol gallstones.…”

Section: Discussionmentioning

confidence: 99%

Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma

Lim

Choi

Kang

2010

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is resistant to chemotherapy. Recently, however, several oxaliplatin-based combinatorial treatments have shown a promising anti-tumor activity in patients with HCC. Presently, we demonstrate that oxaliplatin triggers necrosis more than apoptosis in HepG2, SK-Hep1, SNU-423 and Hep3B HCC cells, while mainly inducing apoptosis in HCT116 and HT29 colon cancer cells. Interestingly, ursodeoxycholic acid (UDCA), a less hydrophobic bile acid that can suppress carcinogenesis, shifted oxaliplatin-induced necrosis to apoptosis in HepG2 cells. The same effect was produced by hydrophilic bile acids (tauroursodeoxycholic acid and taurohyodeoxycholic acid), but not by highly hydrophobic bile acids (deoxycholic acid and chenodeoxycholic acid). UDCA also triggered the necrosis-to-apoptosis switch when cotreated with other platinum-based chemotherapeutic drugs including cisplatin and carboplatin, suggesting that the cell death mode switching effect of UDCA is a general phenomenon when combined with platinum drugs. Oxaliplatin produced high level of reactive oxygen species (ROS) in HepG2 cells and UDCA significantly reduced oxaliplatin-induced ROS generation. In addition, N-acetyl-L-cysteine and the superoxide scavengers butylated hydroxyanisole and dihydroxybenzene-3,5-disulfonic acid attenuated necrosis, indicating a critical role(s) of ROS in occurrence of necrotic death. Apoptosis induced by combined treatment appeared to be mediated by p53-caspase 8-caspase 3 pathway. In conclusion, UDCA switches oxaliplatin-induced necrosis to apoptosis via inhibition of ROS production and activation of the p53-caspase 8 pathway in HepG2 cells. As necrosis and subsequent inflammation are implicated in tumor progression and malignancy, our results imply a potential improved efficacy of UDCA-combined chemotherapy in HCC by reducing inflammatory responses that may be triggered by oxaliplatin.Hepatocellular carcinoma (HCC) is one of the most common malignancies and the leading causes of cancer-related mortality, and it generally represents highly resistant features to chemotherapy.1-3 Surgical resection and liver transplantation might be the most effective way to cure the cancer, but these approaches have limited applicability and advanced tumors frequently recur even after complete surgical resection. 4,5 Hence, chemotherapy remains an important option to treat HCC and developments of new chemotherapeutic strategies are necessary.Oxaliplatin, a third generation platinum-based chemotherapeutic agent, displays a broader spectrum of antitumor activity than cisplatin and carboplatin and no cross-resistance against some cisplatin-and carboplatin-resistant tumors. [6][7][8][9] Currently, it is widely used as a basis of combination regimens for various cancers including gastric, colorectal and advanced nasopharyngeal carcinoma. [10][11][12] In addition, several oxaliplatin-combined regimens have been used for patients with advanced HCC and these have shown a moderate but promising anti-tumor effect. 13,14

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Section: Discussionmentioning

confidence: 99%

Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma

Lim

Choi

Kang

2010

Intl Journal of Cancer

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“…1,38 A recent study showed that UDCA, via activation of the epidermal growth factor receptor and MAPK, induces a survival signal in hepatocytes that may contribute to the antiapoptotic effect. 39 Although intriguing, the impact of antiapoptotic mechanisms for the beneficial effects of UDCA in cholestatic liver disease remains unclear at present.…”

Section: Protection Against Bile Acid-induced Apoptosismentioning

confidence: 99%

Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

Paumgartner¹

2002

Hepatology

649

387

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“…4 Recently, we reported that treatment of primary rodent or human hepatocytes with deoxycholic acid (DCA) caused ligand-independent activation of ERBB1 (EGF receptor), which was responsible for activation of the ERK1/2 and AKT pathways. [5][6][7] In addition to ERBB1, bile acids also have been shown to induce ligand-independent activation of the insulin receptor, but not the insulin-like growth factor 1 receptor, in primary rodent hepatocytes. 8 Activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway by DCA was more strongly linked to activation of the insulin receptor than to ERBB1.…”

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confidence: 99%

Conjugated bile acids promote ERK1/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes

et al. 2005

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Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes

Cited by 132 publications

References 46 publications

Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma

Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma

Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

Conjugated bile acids promote ERK1/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes

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