Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities.
The Rho/ROCK pathway is involved in numerous pivotal cellular processes that have made it an area of intense study in cancer medicine, however, Rho-associated coiled-coil containing protein kinase (ROCK) inhibitors are yet to make an appearance in the clinical cancer setting. Their performance as an anti-cancer therapy has been varied in pre-clinical studies, however, they have been shown to be effective vasodilators in the treatment of hypertension and post-ischaemic stroke vasospasm. This review addresses the various roles the Rho/ROCK pathway plays in angiogenesis, tumour vascular tone and reciprocal feedback from the tumour microenvironment and explores the potential utility of ROCK inhibitors as effective vascular normalising agents. ROCK inhibitors may potentially enhance the delivery and efficacy of chemotherapy agents and improve the effectiveness of radiotherapy. As such, repurposing of these agents as adjuncts to standard treatments may significantly improve outcomes for patients with cancer. A deeper understanding of the controlled and dynamic regulation of the key components of the Rho pathway may lead to effective use of the Rho/ROCK inhibitors in the clinical management of cancer.
The Kinghorn Cancer Centre,Cancer Division,Garvan Institute of Medical Research,384 Victoria St,Darlinghurst,Sydney,NSW 2010,Australia.
Venessa T
VT
Chin
The Kinghorn Cancer Centre,Cancer Division,Garvan Institute of Medical Research,384 Victoria St,Darlinghurst,Sydney,NSW 2010,Australia.
Adnan M
AM
Nagrial
The Kinghorn Cancer Centre,Cancer Division,Garvan Institute of Medical Research,384 Victoria St,Darlinghurst,Sydney,NSW 2010,Australia.
Angela
A
Chou
The Kinghorn Cancer Centre,Cancer Division,Garvan Institute of Medical Research,384 Victoria St,Darlinghurst,Sydney,NSW 2010,Australia.
Andrew V
AV
Biankin
Department of Anatomical Pathology,Royal North Shore Hospital,St Leonards,Sydney,NSW 2065,Australia.
Anthony J
AJ
Gill
The Kinghorn Cancer Centre,Cancer Division,Garvan Institute of Medical Research,384 Victoria St,Darlinghurst,Sydney,NSW 2010,Australia.
Paul
P
Timpson
The Kinghorn Cancer Centre,Cancer Division,Garvan Institute of Medical Research,384 Victoria St,Darlinghurst,Sydney,NSW 2010,Australia.
Marina
M
Pajic
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D058492:Drug Repositioning; D005720:Gamma Rays / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D015398:Signal Transduction; D059016:Tumor Microenvironment; D014665:Vasodilator Agents / Q000627:therapeutic use; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D014665:Vasodilator Agents; D054460:rho-Associated Kinases