Elsevier

Drug Discovery Today

Volume 24, Issue 4, April 2019, Pages 1059-1065
Drug Discovery Today

Review
Post screen
Can cardiovascular drugs support cancer treatment? The rationale for drug repurposing

https://doi.org/10.1016/j.drudis.2019.03.010Get rights and content

Highlights

  • Cardiology drugs have anticancer effect.

  • The renin-angiotensin system contributes to carcinogenesis.

  • Beta blockers attenuate cancer migration.

  • Heparins inhibit cancer spread.

  • Statins exert chemopreventive effect.

Research on the concept of biological overlap between cardiovascular and oncological diseases is gaining momentum. In fact, in both conditions, the malfunction of common regulatory mechanisms, such as the renin-angiotensin system (RAS), sympathetic nervous system (SNS), coagulation cascade, sodium-potassium ATP-ases, and mevalonate pathway, occurs. Thus, targeting these mechanisms with well-known cardiology drugs, including angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), β-adrenergic receptor blockers, statins, cardiac glycosides (CGs), and low-molecular-weight heparins (LMWHs), could be a novel, promising adjuvant strategy in cancer management. Thus, here we discuss the idea of repurposing cardiology drugs in oncology based on available preclinical and clinical data.

Introduction

According to the WHO, cancer and cardiovascular diseases are currently two main causes of mortality worldwide, with an explicit tendency towards increasing incidence and growing social burden over the next 30 years [1]. As per epidemiological estimates, most of this trend stems from the improvement of corresponding survival rates and prolonging human life-expectancy, consequently leading to the formation and continuous growth of the population affected by both diseases concomitantly. It is not only common epidemiological aspects that underlay the frequent coexistence of cancer and cardiovascular conditions. In fact, accumulating clinical and preclinical data also suggest their interdependence and biological overlap, based primarily on their aging-related nature and pathophysiological links [2]. Thus, cancer was recently recognized as an evolutionary adaptive form capable of exploiting host cardiovascular-regulating mechanisms, such as RAS, β-adrenergic system, coagulation system, and sodium/potassium (Na+/K+)-ATP-ase pump system, to promote its own survival. Consistently with these assumptions, various cardiovascular system-normalizing drugs have been found to exhibit documented anticancer activity, including angiotensin-modulating agents, β-antagonists, statins, CGs, and LMWHs, which has suggested their potential repurposing in oncological adjuvant contexts (Fig. 1) [3]. Interestingly, the concept of drug repositioning from noncancer indications to new uses in oncology is a well-established and cost-effective strategy that has already succeeded in introducing aspirin and celecoxib into the prophylaxis of colorectal cancer (CRC) as well as thalidomide into the treatment of multiple myeloma (MM) [4]. Thus, in a specific group of cardio-oncological patients, optimization of cardiological regimens could support the management of coexisting malignancies and improve their performance. Here, we discuss this issue in more detail.

Section snippets

Anti-RAS strategies

Extensive experimental evidence has uncovered the role of RAS in malignant transformation and progression, and this relationship was recently reviewed elsewhere [5]. Here, we present general aspects to provide a background for further discussion. In a typical cancer context, overactivation of RAS occurs in response to a neoplastic adaptive mechanism, leading to the amplification of proproliferatory, proangiogenic, promigratory, proinflammatory, and antiapoptotic responses in malignant cells and

Suppression of sympathetic nervous system

Not only RAS overactivation, but also a well-established association between malignancy and inflammation is an aspect of cancer biology that provides the opportunity for cardiovascular drug repurposing. More specifically, the pathophysiological background behind this concept focuses on the correlation between chronic stress, inflammation, and the accumulation of catecholamines, which further translates into sustained overstimulation of the SNS, which promotes carcinogenesis. Indeed, many

Statins and mevalonate pathway

Another group of cardiovascular agents that could facilitate the pharmacotherapy of neoplastic conditions is statins. The molecular mechanism underlying their eventual role in this area is interference with the formation of mevalonic acid, which further interrupts the biosynthesis of isoprenoids [i.e., farnesyl pyrophosphate (FPP) and geranyl-geranyl phosphate (GGPP)]. Both of these are essential for the biological activation of small G proteins, including Ras, Rac, and Rho, whereas their

Beyond anticoagulant

Subsequent agents capable of supporting anticancer treatment are LMWHs; here, the idea of their reprofiling was developed on the grounds of the recognized relationship between malignancy and thrombosis. Currently, LMWHs are recommended for the supportive care of patients with cancer as a first-line prophylaxis and treatment of thromboembolic events. Although their survival benefit in this indication remains controversial, as well as tumour and agent specific, their potential appears to reach

Cardiac glycosides

Ultimately, CGs also exhibit pleiotropic anticancer activity, which makes them possible candidates for repurposing program in oncology. In fact, the primary rationale suggesting their potential link with neoplasia treatment has been identified as increased expression of their main pharmacodynamic target [sodium/potassium (Na+/K+)-ATPase] in several cancer models, such as NSCLC, gastric, bladder, and RCC 3, 57. In addition, further preclinical tests have shown that CGs exert reproducible,

Concluding remarks

The above discussion confirms that our understanding of the interactions between cancer and cardiovascular diseases is relatively limited and, hence, the potential of cardiology drugs in oncology remains clinically untapped. In fact, most available clinical data originate from retrospective and small prospective studies with a low level of evidence, which are potentially biased (summarized in Table 1). Therefore, no definitive recommendations can be made until directed, randomized, controlled

References (67)

  • J. Kopecka

    A LDL-masked liposomal-doxorubicin reverses drug resistance in human cancer cells

    J. Control. Release

    (2011)
  • M.M. Badran

    Pravastatin-loaded chitosan nanoparticles: formulation, characterization and cytotoxicity studies

    J. Drug Deliv. Sci. Technol.

    (2016)
  • A. Lazo-Langner

    The effect of low-molecular-weight heparin on cancer survival: A systematic review and meta-analysis of randomized trials

    J. Thromb. Haemost.

    (2007)
  • M. Altinbas

    A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer

    J. Thromb. Haemost.

    (2004)
  • L. Ek

    Randomized phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small-cell lung cancer: the RASTEN trial

    Ann. Oncol.

    (2018)
  • D. Sanford

    The effect of low molecular weight heparin on survival in cancer patients: an updated systematic review and meta-analysis of randomized trials

    J. Thromb. Haemost.

    (2014)
  • C. Cerella

    Assembling the puzzle of anti-cancer mechanisms triggered by cardiac glycosides

    Mitochondrion

    (2013)
  • C. Riganti

    Digoxin and ouabain induce P-glycoprotein by activating calmodulin kinase II and hypoxia-inducible factor-1α in human colon cancer cells

    Toxicol. Appl. Pharmacol.

    (2009)
  • WHO

    Key Facts: What Causes Cancer?

    (2018)
  • J. Ishida

    Repurposing of approved cardiovascular drugs

    J. Transl. Med.

    (2016)
  • K. Regulska

    The renin-angiotensin system as a target of novel anticancer therapy

    Curr. Pharm. Des.

    (2013)
  • M. Pinter et al.

    Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy

    Sci. Transl. Med.

    (2017)
  • Y. Zhao

    Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma

    Proc. Natl. Acad. Sci. U. S. A.

    (2019)
  • Y.-Y. Chiang

    Lowered cancer risk with ACE inhibitors/ARBs: a population-based cohort study

    J. Clin. Hypertens.

    (2014)
  • C.-M. Ho

    Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chemoprevention of hepatocellular carcinoma: a nationwide high-risk cohort study

    BMC Cancer

    (2018)
  • FDA

    FDA Drug Safety Communication: No Increase in Risk of Cancer with Certain Blood Pressure Drugs – Angiotensin: Facts about Angiotensin Receptor Blockers

    (2011)
  • B.M. Hicks

    Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study

    BMJ

    (2018)
  • J.E. Murphy

    TGF-B1 inhibition with losartan in combination with FOLFIRINOX (F-NOX) in locally advanced pancreatic cancer (LAPC): preliminary feasibility and R0 resection rates from a prospective phase II study

    J. Clin. Oncol.

    (2017)
  • C. Happold

    Do statins, ACE inhibitors or sartans improve outcome in primary glioblastoma?

    J. Neurooncol.

    (2018)
  • S.W. Cole

    Sympathetic nervous system regulation of the tumour microenvironment

    Nat. Rev. Cancer

    (2015)
  • B.W. Renz

    β2 adrenergic-neurotrophin feedforward loop promotes pancreatic cancer

    Cancer Cell

    (2018)
  • S.W. Cole et al.

    Molecular pathways: beta-adrenergic signaling in cancer

    Clin. Cancer Res.

    (2012)
  • C.-C. Chin

    Selective β2-ar blockage suppresses colorectal cancer growth through regulation of EGFR-Akt/ERK1/2 signaling, G1-phase arrest, and apoptosis

    J. Cell Physiol.

    (2016)
  • Cited by (30)

    • Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions

      2022, Acta Pharmaceutica Sinica B
      Citation Excerpt :

      Repurposing old drugs for antitumor therapy is an effective and economical way to develop new anticancer drugs. According to their original indications, we summarized these repurposing non-oncology small-molecule drugs for cancer therapy (Table 117–114). Several experimental studies have demonstrated that drugs approved by FDA, which are commonly prescribed for the treatment or prevention of cardiovascular diseases, have promising anticancer properties115.

    View all citing articles on Scopus
    View full text