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

Abstract

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

To Be Or Not to Be: the “Smoker’s Paradox” – An in-Vitro Study

“…Compared to the control, hypoxia did not reduce ATP availability in those incubated with low-dose CSE, implicating ATP presence as mode of apoptosis-necrosis switch similar as previously described [34,35]. Moreover, Lim et al reported a switch from necrosis to apoptosis based on inhibition of ROS production in hepatocellular carcinoma [36]. We observed significant lower presence of ROS in hypoxia unaffected by CSE incubation.…”

Neuroprotective activities of curcumin and quercetin with potential relevance to mitochondrial dysfunction induced by oxaliplatin

“…A major clinical issue affecting 10-40 % of patients treated with oxaliplatin is severe peripheral neuropathy causing sensory, motor, and autonomic dysfunction, with symptoms including cold sensitivity and neuropathic pain (Al Moundhri et al 2013). The treatment of brain mitochondria with Oxa provokes several responses including membrane peroxidation and dysfunction of the mitochondria Lim et al 2010). In the current study, we investigated the plausible role of mitochondrial oxidative stress and respiratory chain mechanisms in Oxa-induced brain mitochondrial toxicity.…”

Tumor-Related Molecular Mechanisms of Oxaliplatin Resistance

“…76). It has been demonstrated that oxaliplatin can activate both apoptosis and necrosis depending on the cellular model (77). Although there is a lack of literature about it, in a recent work from Grassilli and colleagues, it was demonstrated that glycogen synthase 3 b (GSK3B), a serine-threonine kinase belonging to the glycogen synthase kinase subfamily that is involved in energy metabolism, neuronal cell development, and body pattern formation, was activated in almost 50% of colon carcinomas and in two thirds of drug-resistant ones.…”