ReviewPost screenCan cardiovascular drugs support cancer treatment? The rationale for drug repurposing
Graphical abstract
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
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