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Poster display session

5449 - Enhanced Antitumor Activity of Fixed-dose Combinations of Celecoxib and Antihypertensives

Date

11 Sep 2017

Session

Poster display session

Presenters

Cynthia Lee

Citation

Annals of Oncology (2017) 28 (suppl_5): v573-v594. 10.1093/annonc/mdx390

Authors

C. Lee1, L. Hwang2, O. D'Cruz1, K. Ng1, V. Trieu2

Author affiliations

  • 1 Clinical Research, Autotelic Inc., 92626 - Costa Mesa/US
  • 2 Clinical Research, Marina Biotech, 91748 - City of Industry/US
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Resources

Abstract 5449

Background

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.

Methods

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.

Results

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.

Conclusions

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

Funding

None

Disclosure

All authors have declared no conflicts of interest.

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