Excerpt
The cardio-oncology is experiencing the era of targeted cancer therapies. Research identified novel therapeutic targets in cancer: human ether-a-go-go-related gene K (+) channels [HERGs] [
1], epidermal growth factor receptors (EGFRs) [
2], and vascular endothelial growth factor receptors (VEGFs) [
1]. Related therapies have been developed [
1,
2] with high cost and conflicting viewpoints [
3,
4]. Quinazoline is a compound made up of two fused six member simple aromatic rings – the benzene & pyrimidine ring [
5] - with several biological effects. The search for quinazoline-based substances as cardiovascular agents begun after pharmacological screening of hypotensive activity of quinazoline that has a glycine amide or β-alanine amide residue in 3rd position. Other quinazoline derivatives have also demonstrated significant anticancer activities [
5,
6] and new molecules have been synthesized [
7]. Gefitinib, erlotinib, and afatinib are orally effective protein-kinase targeted quinazoline derivatives that are used in the treatment of ERBB1-mutant lung cancer. Lapatinib is an orally effective quinazoline derivative used in the treatment of ErbB2-overexpressing breast cancer [
7]. Cardiology first used the quinazoline-based α (1) -adrenoceptor antagonists prazosin, doxazosin, and terazosin and currently available data have supported the use of quinazoline-based α (1)-adrenoceptor antagonist as safe, well tolerated and effective add-on therapy in uncontrolled hypertension with additional favourable metabolic effects [
8]. New data from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) suggest that doxazosin gastrointestinal therapeutic system (GITS) is not associated with an increased risk of heart failure, in contrast to the earlier finding of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [
8‐
10] and research suggests an adverse cardiac effect with doxazosin only among patients with moderate-to-severe ischemia on myocardial perfusion imaging [
11]. Novel findings have indicated that the small molecule antihypertensive alpha1-adrenoceptor antagonist quinazoline-based [
6] doxazosin is a human ether-a-go-go-related gene K (+) channels [HERG] ligand [
12], an epidermal growth factor receptor (EGFR) inhibitor [
13], a vascular endothelial growth factor (VEGF)-mediated angiogenic response antagonist [
14], and a fibroblast growth factor-2 (FGF-2) antagonist [
14,
15]. In addition, doxazosin [
6] is capable of inhibiting malignant behaviours in vitro and in vivo and it is also an agonist of a receptor tyrosine kinase triggering ephrin type-A receptor 2 [EphA2] internalization suppressing haptotactic and chemotactic migration of prostate cancer, breast cancer, and glioma cells [
16]. Doxazosin also prevents p27 downregulation [
17] and may partly reverse P-glycoprotein/MDR1-mediated cancer multidrug resistance (CMDR) and the transport of anticancer drugs [
18]. The antihypertensive alpha1-adrenoceptor antagonist [
19] quinazoline-based [
6] antihypertensive terazosin is a HERG ligand [
20] and terazosin induces cell death, associated with G1 phase cell cycle arrest, and up-regulation of cyclin-dependent kinase inhibitor 1B (p27KIP1) [
21]. The antihypertensive alpha1-adrenoceptor antagonist [
21] quinazoline-based [
6] prazosin is a HERG ligand [
20] and EGFR inhibitor [
22] . Prazosin induces autophagic cell death via a p53-mediated mechanism [
23] and cell apoptosis through the induction of DNA damage stress, leading to cyclin-dependent kinase (Cdk) 1 inactivation and G2 checkpoint arrest triggering mitochondria-mediated inducing apoptosis [
24]. In addition prazosin exhibits anti-angiogenic activity [
25]. These emerging findings indicate that the antihypertensive alpha1-adrenoceptor antagonists quinazoline-based drugs may have a significant role [
6,
13] in uncontrolled hypertensive cancer patients without signs of ischemia [
6,
9,
11]. …
