The Use of Antihypertensive Drugs as Coadjuvant Therapy in Cancer

Abstract

Cancer is a complex group of diseases that constitute the second largest cause of mortality worldwide. The development of new drugs for treating this disease is a long and costly process, from the discovery of the molecule through testing in phase III clinical trials, a process during which most candidate molecules fail. The use of drugs currently employed for the management of other diseases (drug repurposing) represents an alternative for developing new medical treatments. Repurposing existing drugs is, in principle, cheaper and faster than developing new drugs. Antihypertensive drugs, primarily belonging to the pharmacological categories of angiotensin-converting enzyme inhibitors, angiotensin II receptors, direct aldosterone antagonists, β-blockers and calcium channel blockers, are commonly prescribed and have well-known safety profiles. Additionally, some of these drugs have exhibited pharmacological properties useful for the treatment of cancer, rendering them candidates for drug repurposing. In this review, we examine the preclinical and clinical evidence for utilizing antihypertensive agents in the treatment of cancer.

Keywords: Renin – Angiotensin – Aldosterone System; antihypertensive agents; cancer; cancer therapy; repurposable drugs.

Figure 1

Antihypertensive drugs: General overview. Blood pressure can be determined by changes in cardiac output, total peripheral resistance and intravascular volume. The Renin Angiotensin System is one of the key regulators of blood pressure, it works by increasing Angiotensin II, a powerful systemic vasoconstrictor and one of the main intravascular volume regulators. Angiotensin II works by activating Angiotensin II receptors, which are G-Coupled. Angiotensin II works hand-in-hand with aldosterone to promote sodium and water reabsorption, and hence, maintaining intravascular volume as needed. The heart as a pump, is another blood pressure regulator, it modulates important variables such as Stroke Volume and Heart Rate, which are an important influence for Cardiac Output. Several drugs can lower blood pressure by inhibiting different physiological mechanisms shown in this figure. RI, Renin Inhibitors; ACE, Angiotensin converting enzyme; ACEI, Angiotensin converting enzyme Inhibitors; CCB, Calcium-Channel Blockers.

Figure 2

Antihypertensive drugs: Antitumoral mechanisms. In this figure we summarize potential mechanisms in which antihypertensive drugs may aid oncologic therapies throughout different cellular effects schematized in the figure. Ag II, Angiotensin II; Epi, Epinephrine; NFkB, Nuclear factor kappa B; VEGF, Vascular Endothelial Growth Factor; HIFα, Hipoxia Induced Factor Alpha; ARB, Angiotensin II Receptor Blockers; BB, Beta Blockers; CCB, Calcium Channel Blockers.