Abstract
Esophageal squamous cell carcinoma (ESCC) is a frequently diagnosed and deadly malignancy with few standard therapeutic options. Camptothecins are considered one of the most promising antitumor drugs. A modified lipophilic analog, gimatecan, was synthesized as a novel oral camptothecin and showed impressive effects in various tumors, but its therapeutic efficacy and mechanisms in ESCC remain unclear. This study investigated the antitumor efficacy and mechanisms of gimatecan in ECSS both in vitro and in vivo. Using ESCC cell lines, cell line-derived xenografts and patient-derived xenografts models, we evaluated gimatecan’s inhibition of tumor growth, and compared its antitumor efficacy with that of irinotecan. Topoisomerase I function and expression were assessed using the DNA relaxation assay and Western blotting, respectively. DNA damage was evaluated by Western blotting. Cell cycle progression and cell apoptosis were assessed using flow cytometry and Western blotting. Gimatecan could significantly suppress tumor growth in vivo and inhibit tumor cell proliferation in vitro, which was superior to irinotecan. Gimatecan suppressed the function and expression of topoisomerase I. It also caused DNA damage and activated the phosphorylation of multiple checkpoint gatekeepers, such as ATM, ATR, BRCA1, H2AX, CHK1, CHK2, and p53. It induced S phase arrest, enhanced the expression of p21WAF1/CIP, and suppressed the expression of CDK2 and cyclin A. Induction of apoptosis was accompanied by increases in Bax, cleaved-caspase 3 activation, cleaved-caspase 9 induction, and a decrease in Bcl-2. The molecular and phenotypic changes induced by gimatecan were stronger than that of irinotecan. In ESCC, gimatecan suppressed the expression and function of topoisomerase I, induced DNA damage and intra-S phase cell cycle arrest, and resulted in apoptosis. And the results suggest that gimatecan has higher potency in inhibiting ESCC tumor growth than irinotecan, providing a rational novel therapeutic strategy for future clinical evaluation.
Highlights
Esophageal cancer (EC) is the fourth most commonly diagnosed and the most fatal cancer in China[1]
Compared to the control group, tumor growth was significantly suppressed in gimatecan-treated groups (TGIs were 94%, 136%, 112%, 105%, and 81% in five cases, all p < 0.01) (Fig. 1a–e)
Gimatecan inhibited the proliferation of multiple EC cell lines, suppresses topoisomerase I activity, induced DNA damage, arrest cell cycle, caused cell apoptosis, and repressed tumor growth in mice models more significantly than irinotecan, demonstrating that it might potentially be a more powerful anticancer agent than irinotecan
Summary
Esophageal cancer (EC) is the fourth most commonly diagnosed and the most fatal cancer in China[1]. Esophageal squamous cell carcinoma (ESCC) is the predominant histological type of EC, comprising more than 95% of all EC cases[2]. ESCC is considered an aggressive malignancy due to the poor prognosis and high mortality rate. Zou et al Cell Death and Disease (2018)9:661 patients that are diagnosed with locally advanced or metastatic ESCC at the time of initial diagnosis[3,4] are unable to undergo radical surgery, so the mainstays of treatment for these patients are radiation therapy and chemotherapy. The prognosis for patients with ESCC is still poor, with a 5-year survival rate of only about 20%3. It is crucial to identify the novel therapeutic alternatives or agents for patients with ESCC
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