Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo
Abstract Background Tumor hypoxia is considered an important factor in metastasis and disease relapse. Evofosfamide is a hypoxia-activated prodrug that selectively targets the hypoxic regions of solid tumors. As hypoxia-inducible factor-1α (HIF-1α) is overexpressed in nasopharyngeal carcinoma (NPC)...
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doaj-ce49a45d99824ecab265abddc943829a2020-11-25T03:32:56ZengWileyCancer Communications2523-35482018-05-013811910.1186/s40880-018-0285-0Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivoYan Huang0Ying Tian1Yuanyuan Zhao2Cong Xue3Jianhua Zhan4Lin Liu5Xiaobo He6Li Zhang7State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, The Fifth Affiliated Hospital, Sun Yat-Sen UniversityDepartment of Radiation Oncology, The Fifth Affiliated Hospital, Sun Yat-Sen UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer CenterAbstract Background Tumor hypoxia is considered an important factor in metastasis and disease relapse. Evofosfamide is a hypoxia-activated prodrug that selectively targets the hypoxic regions of solid tumors. As hypoxia-inducible factor-1α (HIF-1α) is overexpressed in nasopharyngeal carcinoma (NPC) tissues, we performed the present study to evaluate the efficacy profile of evofosfamide in NPC. Methods We evaluated the efficacy of evofosfamide as a single agent or combined with cisplatin (DDP) in the NPC cell lines CNE-2, HONE-1 and HNE-1, and in nude mouse xenograft tumor models. Results Evofosfamide exhibited hypoxia-selective cytotoxicity in NPC cell lines, with 50% inhibition concentration (IC50) values of 8.33 ± 0.75, 7.62 ± 0.67, and 0.31 ± 0.07 μmol/L under hypoxia in CNE-2, HONE-1 and HNE-1 cells, respectively. The sensitization ranged from ninefold to greater than 300-fold under hypoxia compared with normoxia controls. The combination of evofosfamide with DDP had a synergistic effect on cytotoxicity in the NPC cell lines by combination index values assessment. Cell cycle G2 phase was arrested after treated with 0.05 μmol/L evofosfamide under hypoxia. Histone H2AX phosphorylation (γH2AX) (a marker of DNA damage) expression increased while HIF-1α expression suppressed after evofosfamide treatment under hypoxic conditions. In the HNE-1 NPC xenograft models, evofosfamide exhibited antitumor activity both as a single agent and combined with DDP. Hypoxic regions in xenograft tissue were reduced after both evofosfamide monotherapy and combined therapy with DDP. Conclusions Our results present preclinical evidence for targeting the selective hypoxic portion of NPC by evofosfamide as a single agent and combined with DDP and provide rationale for the potential clinical application of evofosfamide for the treatment of nasopharyngeal carcinoma.http://link.springer.com/article/10.1186/s40880-018-0285-0Nasopharyngeal carcinoma (NPC)Hypoxia-induced factor-1α (HIF-1α)Hypoxia-activated prodrugChemotherapyXenograft tumor models |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yan Huang Ying Tian Yuanyuan Zhao Cong Xue Jianhua Zhan Lin Liu Xiaobo He Li Zhang |
spellingShingle |
Yan Huang Ying Tian Yuanyuan Zhao Cong Xue Jianhua Zhan Lin Liu Xiaobo He Li Zhang Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo Cancer Communications Nasopharyngeal carcinoma (NPC) Hypoxia-induced factor-1α (HIF-1α) Hypoxia-activated prodrug Chemotherapy Xenograft tumor models |
author_facet |
Yan Huang Ying Tian Yuanyuan Zhao Cong Xue Jianhua Zhan Lin Liu Xiaobo He Li Zhang |
author_sort |
Yan Huang |
title |
Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo |
title_short |
Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo |
title_full |
Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo |
title_fullStr |
Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo |
title_full_unstemmed |
Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo |
title_sort |
efficacy of the hypoxia-activated prodrug evofosfamide (th-302) in nasopharyngeal carcinoma in vitro and in vivo |
publisher |
Wiley |
series |
Cancer Communications |
issn |
2523-3548 |
publishDate |
2018-05-01 |
description |
Abstract Background Tumor hypoxia is considered an important factor in metastasis and disease relapse. Evofosfamide is a hypoxia-activated prodrug that selectively targets the hypoxic regions of solid tumors. As hypoxia-inducible factor-1α (HIF-1α) is overexpressed in nasopharyngeal carcinoma (NPC) tissues, we performed the present study to evaluate the efficacy profile of evofosfamide in NPC. Methods We evaluated the efficacy of evofosfamide as a single agent or combined with cisplatin (DDP) in the NPC cell lines CNE-2, HONE-1 and HNE-1, and in nude mouse xenograft tumor models. Results Evofosfamide exhibited hypoxia-selective cytotoxicity in NPC cell lines, with 50% inhibition concentration (IC50) values of 8.33 ± 0.75, 7.62 ± 0.67, and 0.31 ± 0.07 μmol/L under hypoxia in CNE-2, HONE-1 and HNE-1 cells, respectively. The sensitization ranged from ninefold to greater than 300-fold under hypoxia compared with normoxia controls. The combination of evofosfamide with DDP had a synergistic effect on cytotoxicity in the NPC cell lines by combination index values assessment. Cell cycle G2 phase was arrested after treated with 0.05 μmol/L evofosfamide under hypoxia. Histone H2AX phosphorylation (γH2AX) (a marker of DNA damage) expression increased while HIF-1α expression suppressed after evofosfamide treatment under hypoxic conditions. In the HNE-1 NPC xenograft models, evofosfamide exhibited antitumor activity both as a single agent and combined with DDP. Hypoxic regions in xenograft tissue were reduced after both evofosfamide monotherapy and combined therapy with DDP. Conclusions Our results present preclinical evidence for targeting the selective hypoxic portion of NPC by evofosfamide as a single agent and combined with DDP and provide rationale for the potential clinical application of evofosfamide for the treatment of nasopharyngeal carcinoma. |
topic |
Nasopharyngeal carcinoma (NPC) Hypoxia-induced factor-1α (HIF-1α) Hypoxia-activated prodrug Chemotherapy Xenograft tumor models |
url |
http://link.springer.com/article/10.1186/s40880-018-0285-0 |
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