Irinotecan as first-line chemotherapy in patients with advanced hepatocellular carcinoma: A multicenter phase II study with dose adjustment according to baseline serum bilirubin level

Talati

J. Gastrointest. Oncol.

2017

255

168

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with poor prognosis.The incidence of HCC and HCC-related deaths have increased over the last several decades. However, the treatment options for advanced HCC are very limited. Sorafenib remains the only drug approved for systemic treatment for advanced HCC. However, prior to sorafenib era conventional cytotoxic chemotherapies have been studied in advanced HCC. In this review, clinical studies of systemic chemotherapy for advanced HCC will be summarized and discussed.

Section: Irinotecanmentioning

confidence: 99%

Hepatocellular carcinoma (HCC): beyond sorafenib—chemotherapy

Talati

J. Gastrointest. Oncol.

2017

255

168

Molecular Cancer Therapeutics

“…During DNA replication, the replication fork is thought to collide with the "trapped" topoisomerase I-DNA complexes, resulting in double-strand breaks and ultimately cell death. Irinotecan is a topoisomerase I inhibitor registered for the treatment of gastrointestinal cancer in humans and has been shown to exert activity on many cancer cell lines in vitro, but it fails to provide definitive information in vivo, particularly through intravenous infusion in patients with hepatocellular carcinoma (18). Similar to other cancer types, hepatocellular carcinoma progresses and develops drug resistance via the upregulation of stress-induced molecules such as HIF-1a.…”

Section: Introductionmentioning

confidence: 99%

Tirapazamine Sensitizes Hepatocellular Carcinoma Cells to Topoisomerase I Inhibitors via Cooperative Modulation of Hypoxia-Inducible Factor-1α

Cai

Liu

Zhu

et al. 2014

Topoisomerase I inhibitors are a class of anticancer drugs with a broad spectrum of clinical activity. However, they have limited efficacy in hepatocellular cancer. Here, we present in vitro and in vivo evidence that the extremely high level of hypoxia-inducible factor-1a (HIF-1a) in hepatocellular carcinoma is intimately correlated with resistance to topoisomerase I inhibitors. In a previous study conducted by our group, we found that tirapazamine could downregulate HIF-1a expression by decreasing HIF-1a protein synthesis. Therefore, we hypothesized that combining tirapazamine with topoisomerase I inhibitors may overcome the chemoresistance. In this study, we investigated that in combination with tirapazamine, topoisomerase I inhibitors exhibited synergistic cytotoxicity and induced significant apoptosis in several hepatocellular carcinoma cell lines. The enhanced apoptosis induced by tirapazamine plus SN-38 (the active metabolite of irinotecan) was accompanied by increased mitochondrial depolarization and caspase pathway activation. The combination treatment dramatically inhibited the accumulation of HIF-1a protein, decreased the HIF-1a transcriptional activation, and impaired the phosphorylation of proteins involved in the homologous recombination repair pathway, ultimately resulting in the synergism of these two drugs. Moreover, the increased anticancer efficacy of tirapazamine combined with irinotecan was further validated in a human liver cancer Bel-7402 xenograft mouse model. Taken together, our data show for the first time that HIF-1a is strongly correlated with resistance to topoisomerase I inhibitors in hepatocellular carcinoma. These results suggest that HIF-1a is a promising target and provide a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and tirapazamine in hepatocellular cancers. Mol Cancer Ther; 13(3); 630-42. Ó2013 AACR.

Biological & Pharmaceutical Bulletin

“…[3][4][5] Sorafenib is a multikinase inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and Raf. It is the only agent that has been shown to improve overall survival and to be well tolerated in subjects with advanced-stage HCC with well-preserved liver function.…”

mentioning

confidence: 99%

Comparison of the Anti-tumor Effects of Selective Serotonin Reuptake Inhibitors as Well as Serotonin and Norepinephrine Reuptake Inhibitors in Human Hepatocellular Carcinoma Cells

Kuwahara

Yamada

Egashira

et al. 2015

The anti-tumor effects of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) on several types of cancer cells have been reported. However, comparison of the anti-tumor effects of these drugs on human hepatocellular carcinoma (HepG2) cells has not been studied. We compared the anti-tumor effects of four SSRIs and two SNRIs on HepG2 cells. SSRIs and duloxetine dose-dependently decreased cell viability. Milnacipran had no effect on cell viability. The half-maximal inhibitory concentration was lower in the order of: sertraline, paroxetine, duloxetine, fluvoxamine, escitalopram, and milnacipran. Exposure to sertraline (2 µM) significantly increased caspase-3/7 activity. These results suggest that, of the agents tested here, sertraline had the highest sensitivity to HepG2 cells, and activation of the caspase pathway is involved in the anti-tumor effects of sertraline in HepG2 cells.Key words selective serotonin reuptake inhibitor; anti-tumor effect; sertraline; serotonin and norepinephrine reuptake inhibitor; human hepatocellular carcinoma cell Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancerbased death.