Increased efficacy of CDDP in a xenograft model of hepatoblastoma using the apoptosis sensitizer ABT-737

Abstract

The response of standard-risk hepatoblastoma (HB) to neoadjuvant cisplatin (CDDP) chemotherapy is excellent; however, in high-risk HB, drug resistance remains a major challenge. Alternative therapeutic strategies may consider combining cytotoxic drugs with apoptosis sensitizers as this has shown additive effects in various types of malignancies. Analysis of published expression databases have revealed an anti-apoptosis state in HB samples. Herein, we evaluated the synergistic effects of ABT-737 as a modulator of apoptosis in combination with CDDP in HB. To this end, clonogenic assays were performed with HepT1 and HUH6 HB cells to evaluate the synergistic effects of CDDP and ABT-737. Combination treatment with CDDP and ABT-737 reduced the clonogenicity of HB cells more than 5-fold compared to treatment with CDDP alone. Furthermore, the HUH6 mixed-type HB cells showed higher sensitivity to CDDP and combination treatment compared to the HepT1 embryonal-type cells. Subcutaneous HUH6 tumors in NOD/LtSz-scid IL2Rγnull mice were treated with CDDP (1.25 and 3 mg/kg body weight, n=6), ABT-737 (100 mg/kg, n=5) and the combination of both agents (n=5). Combined treatment led to a significantly reduced tumor growth compared to CDDP treatment alone (p<0.02). When using higher doses of CDDP (3 mg/kg) alone or in combination with ABT-737, dose-dependent toxicity was observed in this mouse strain. In conclusion, our results demonstrated the enhancement of chemotherapy efficacy by using modulators of apoptosis together with cytotoxic agents. Additive effects of ABT-737 may allow reduction in CDDP dosages with maintenance of antitumor activity. Sensitizing HB to apoptosis may also render resistant HB susceptible to established chemotherapy regimens.

ABT737 reverses cisplatin resistance by regulating ER-mitochondria Ca2+ signal transduction in human ovarian cancer cells

“…ABT-737, a small molecule compound, inhibits Bcl-2 by mimicking the function of the BH3-only protein (31)(32)(33). Using a xenograft model of hepatoblastoma (HB), Lieber et al have reported that ABT737 restores the cisplatin sensitivity of cisplatin-resistant HB cells and significantly decreases tumor growth, as compared with that observed after cisplatin monotherapy (34). Additionally, our previous results have shown that ABT737 enhances cisplatin-induced Bcl-2 downregulation and cisplatin-induced apoptosis through the regulation of mitochondrial dynamics in cholangiocarcinoma cells (25).…”

Mechanisms of Anticancer Drug Resistance in Hepatoblastoma

“…High levels of the anti-apoptotic proteins Bcl-2 and Bcl-XL, as well as low levels of the pro-apoptotic proteins Bax and Bad, were found in HuH6 and HepT1 cell lines [38]. Beside ABC-mediated sensitization, increased efficacy of cisplatin in vitro [39] and in a xenograft model of HB [40] has been reported by using the apoptosis sensitizer ABT-737, which inhibits both Bcl-2 and Bcl-XL. A consistent increase in the expression of survivin ( BIRC5 gene), a member of the inhibitor of apoptosis protein (IAP) family, has been found in liver tumors, such as HB, HCC and cholangiocarcinoma (CCA) [29].…”

The Role of BH3-Mimetic Drugs in the Treatment of Pediatric Hepatoblastoma

“…Inhibition of these proteins using ABT-737 or obatoclax has induced significant reduction of HB cell proliferation [ 61 , 85 ]. It has also been demonstrated that these modulators of apoptosis enhance the effects of cytotoxic drugs in vitro and in vivo , where reduced proliferation rates were documented after combined treatment with ABT-737 and paclitaxel or cisplatin and reduction of tumor growth in a subcutaneous model of HB [ 86 , 87 ]. Other small molecular drugs with BH3-mimetic effect tested on HB cells, such as HA14-1 or TW37, did not show any significant effect as single agents, or in combination with several cytotoxic drugs [ 85 ].…”