Inflammation and hypertension have recently emerged as causal factors for tumor progression and anti-hypertensive agents have been shown to reduce inflammation and suppress tumor growth and metastasis. Cyclooxygenase-2 (COX-2) is upregulated in most human tumors and is a potent inducer of cancer-associated inflammation. This preclinical study evaluated a novel combination of a COX-2 inhibitor with three antihypertensive drugs to suppress tumor growth and metastasis.
Three anti-hypertensive drugs: i) Lisinopril [LIS], an inhibitor of Ang I converting enzyme (ACE); ii) Olmesartan medoxomil (OLM), an Ang II receptor blocker (ARB); and iii) Hydrochlorothiazide (HCTZ), a thiazide diuretic along with Celecoxib [CEL], a COX-2 inhibitor were evaluated either alone or in combination for tumor growth suppression and metastatic spread in an orthotopic inflammatory breast cancer (IBC)/SUM149 model and subcutaneous melanoma/MDA-MB-435, glioblastoma/U87, and IBC/SUM159 models. Luciferase-tagged SUM149 and MDA-MB-435 cell lines were used to determine the incidence and the burden of locoregional and systemic spread. Mice were monitored for weight loss, tumor volume and survival outcome. Metastasis was measured as luciferase expression in lymph nodes and lungs and normalized to total protein.
In the orthotopic SUM149 model, OLM and CEL plus OLM, had a statistically significant decrease in tumor burden (2.4 ± 0.6 x104 RLU/mg of protein, p = 0.01 by Mann-Whitney test) in the ipsilateral lymph nodes versus the saline-treated control (17.6 ± 8.6 x104 RLU/mg of protein). Similar trend was observed for LIS, but not for HCTZ. In the subcutaneous model, synergistic antitumor activity was observed with OLM (p = 0.026) at low dose but not with LIS and CEL (p = ns). At high dose, LIS, OLM, and CEL showed significant inhibition of tumor growth but no synergy. HCTZ, an antihypertensive diuretic which has no direct impact on the vascular wall had no effect on tumor growth.
These preclinical data strongly suggest a hitherto unappreciated role of ACE/ARB in tumor growth control and support the further exploration of combinations of CEL with ACE/ARB in cancer, especially inflammatory breast cancer.
Clinical trial identification
Legal entity responsible for the study
Marina Biotech Inc
All authors have declared no conflicts of interest.