Increasing reactive oxygen species as a therapeutic approach to treat hereditary leiomyomatosis and renal cell carcinoma.
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 cytotoxic effects 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.
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Carole
C
Sourbier
Vladimir
V
Valera-Romero
Alessio
A
Giubellino
Youfeng
Y
Yang
Sunil
S
Sudarshan
Len
L
Neckers
W Marston
WM
Linehan
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000628:therapy*; D016923:Cell Death; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000628:therapy*; D018231:Leiomyomatosis / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011719:Pyrazines / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D017382:Reactive Oxygen Species; D000069286:Bortezomib; D002945:Cisplatin