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Theranostics 2020; 10(15):6959-6976. doi:10.7150/thno.41792 This issue Cite

Research Paper

Up-regulation of hypoxia-inducible factor antisense as a novel approach to treat ovarian cancer

Tiangong Lu^1*, Jianming Tang^1,2*, Binita Shrestha¹, Blake R. Heath³, Li Hong², Yu L. Lei³, Mats Ljungman⁴, Nouri Neamati^1✉

1. Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109-2800, USA
2. Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei province, 430060, P.R. China
3. Departments of Periodontics and Oral Medicine and Otolaryngology- Head and Neck Surgery, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109-2800, USA
4. Department of Radiation Oncology, University of Michigan Medical School, Rogel Cancer Center and Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI 48109-2800, USA
*Contributed equally to this work

✉ Corresponding author: N.N. E-mail: neamatiedu; Phone: 734-647-2732

Abstract

Ovarian cancer (OC) is estimated to kill ~14,000 women in the United States in 2019. Current chemotherapies to treat OC initially show therapeutic efficacy but frequently drug resistance develops, at which point therapies with alternative targets are needed. Herein, we are describing a novel approach to sensitize these tumors to standard chemotherapies by increasing the transcription of hypoxia-inducible factor antisense.

Methods: Genome-wide Bru-seq analysis was performed to fully capture the nascent transcriptional signature of OC cells treated with the gp130 inhibitor, SC144. In vitro and in vivo analysis, including characterization of hypoxia and select protein expression, combination with standard of care chemotherapy and antitumor efficacy were performed to assess the biological activity of SC144 on induction of hypoxia in OC cells.

Results: Bru-seq analysis of OVCAR8 cells treated with SC144 shows upregulation of hypoxia related genes. In addition, transcription of hypoxia-inducible factor antisense (HIF1A-AS2) was induced that in turn reduced expression of HIF-1α and simultaneously increased expression of NDRG1. Furthermore, we observed decreased protein levels of EGFR, Met, c-Myc, cyclin D1, MMP-2, MMP-9 and TF, and phosphorylation of Src and P130-cas. SC144-induced alterations of HIF-1α and NDRG1 were also confirmed in prostate cancer cells. Ciclopirox olamine (CPX) induces a cellular transcriptional profile comparable to SC144, suggesting a similar cellular mechanism of action between these two compounds. In addition, SC144 sensitized OC cells to olaparib, carboplatin and cisplatin, and shows better in vivo efficacy than CPX.

Conclusion: Induction of hypoxic stress responses through inhibition of gp130 represents a novel approach to design effective anticancer treatments in combination with standard-of-care chemotherapy in OC and the efficacy reported here strongly supports their clinical development.

Keywords: SC144, hypoxia, antisense RNA, iron chelators, ovarian cancer

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