Increasing reactive oxygen species as a therapeutic approach to treat hereditary leiomyomatosis and renal cell carcinoma

Carole Sourbier, Vladimir Valera-Romero, Alessio Giubellino, Youfeng Yang, Sunil Sudarshan, Len Neckers, W. Marston Linehan

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Hereditary leiomyomatosis renal cell carcinoma (HLRCC)-associated renal tumors are aggressive and tend to metastasize early. There are currently no effective forms of therapy for patients with advanced HLRCC-associated kidney cancer. We have previously shown that HLRCC cells express a high level of reactive oxygen species (ROS). In the present study we investigated the cytotoxiceffects of increasing ROS level using bortezomib in combination with cisplatin on HLRCC cells in vitro and in an in vivo xenograft model. The cytotoxic effect of several ROS inducers on FH-deficient cells was assessed by synthetic lethality. ROS inducers had a pronounced impact on the viability of FH-deficient cells. Because of its high potency, the proteasome inhibitor bortezomib was further investigated. Bortezomib induced apoptosis in vitro in HLRCC cells and inhibited HLRCC tumour growth in vivo. Bortezomib-associated cytotoxicity was highly correlated with cellular ROS level: combining bortezomib with other ROS inducers enhanced cytotoxicity, while combining bortezomib with a ROS scavenger inhibited its cytotoxic effect. Finally, HLRCC murine xenografts were treated with bortezomib and cisplatin, another ROS inducer. This regimen induced HLRCC tumour regression in vivo. These findings suggest that increasing ROS level in HLRCC above a certain threshold can induce HLRCC-tumor cell death. Increasing tumor ROS with bortezomib in combination with cisplatin represents a novel targeted therapeutic approach to treat advanced HLRCC-associated renal tumors.

Original languageEnglish (US)
Pages (from-to)4183-4189
Number of pages7
JournalCell Cycle
Volume9
Issue number20
DOIs
StatePublished - Oct 15 2010

Bibliographical note

Funding Information:
We wish to thank Dr. B.T. Scroggins for helpful discussions, Ms. Catherine Wells for technical assistance and Ms. G. Shaw for editorial assistance. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Keywords

  • Bortezomib
  • Cisplatin
  • FH
  • HLRCC
  • Kidney cancer
  • ROS

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