Repurposing of α1-Adrenoceptor Antagonists: Impact in Renal Cancer

Mihalopoulos, Meredith; Dovey, Zachary; Archer, Maddison; Korn, Talia G; Okhawere, Kennedy; Nkemdirim, William; Funchess, Hassan; Rambhia, Ami; Mohamed, Nihal; Kaplan, Steven A.; Mehrazin, Reza; Lundon, Dara; Tsao, Che‐Kai; Badani, Ketan K.; Kyprianou, Natasha

doi:10.3390/cancers12092442

Cited by 7 publications

(7 citation statements)

References 45 publications

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“…Other research revealed that human bladder cancer cells are sensitive to the apoptotic effects of terazosin and that bladder tumors exhibit reduced tissue vascularity ( Tahmatzopoulos et al, 2005 ; Martin et al, 2008 ). Recently, the above results have been confirmed by Mihalopoulos and coworkers ( Mihalopoulos et al, 2020 ).…”

Section: Quinazoline Derivatives In Urinary Bladder Cancer Therapysupporting

confidence: 67%

Quinazoline Derivatives as Potential Therapeutic Agents in Urinary Bladder Cancer Therapy

et al. 2021

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Cancer diseases remain major health problems in the world despite significant developments in diagnostic methods and medications. Many of the conventional therapies, however, have limitations due to multidrug resistance or severe side effects. Bladder cancer is a complex disorder, and can be classified according to its diverse genetic backgrounds and clinical features. A very promising direction in bladder cancer treatment is targeted therapy directed at specific molecular pathways. Derivatives of quinazolines constitute a large group of chemicals with a wide range of biological properties, and many quinazoline derivatives are approved for antitumor clinical use, e.g.,: erlotinib, gefitinib, afatinib, lapatinib, and vandetanib. The character of these depends mostly on the properties of the substituents and their presence and position on one of the cyclic compounds. Today, new quinazoline-based compounds are being designed and synthesized as potential drugs of anticancer potency against bladder cancers.

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Section: Quinazoline Derivatives In Urinary Bladder Cancer Therapysupporting

confidence: 67%

Quinazoline Derivatives as Potential Therapeutic Agents in Urinary Bladder Cancer Therapy

et al. 2021

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“…The anoikis-driven antitumor effect of α1-adrenoreceptor antagonists promises a safe-strategy in treating advanced disease—both therapeutically-resistant and castration-sensitive prostate cancer [ 143 , 256 , 257 ]. Quinazoline-based compounds developed after the pharmacological optimization of α1-adrenoceptor antagonists cause phenotypic reversion of EMT to MET and induce anoikis towards overcoming resistance to AR antiandrogens in pre-clinical models of advanced prostate cancer [ 143 , 257 , 258 , 259 ].…”

Section: The Phenotypic Landscape Of Advanced Prostate Cancermentioning

confidence: 99%

Non-Coding RNAs Set a New Phenotypic Frontier in Prostate Cancer Metastasis and Resistance

Altschuler

Stockert

Kyprianou

2021

IJMS

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Prostate cancer (PCa) mortality remains a significant public health problem, as advanced disease has poor survivability due to the development of resistance in response to both standard and novel therapeutic interventions. Therapeutic resistance is a multifaceted problem involving the interplay of a number of biological mechanisms including genetic, signaling, and phenotypic alterations, compounded by the contributions of a tumor microenvironment that supports tumor growth, invasiveness, and metastasis. The androgen receptor (AR) is a primary regulator of prostate cell growth, response and maintenance, and the target of most standard PCa therapies designed to inhibit AR from interacting with androgens, its native ligands. As such, AR remains the main driver of therapeutic response in patients with metastatic castration-resistant prostate cancer (mCRPC). While androgen deprivation therapy (ADT), in combination with microtubule-targeting taxane chemotherapy, offers survival benefits in patients with mCRPC, therapeutic resistance invariably develops, leading to lethal disease. Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes and also to the development of biomarker signatures of predictive value. The interconversions between epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) navigate the prostate tumor therapeutic response, and provide a novel targeting platform in overcoming therapeutic resistance. Both microRNA (miRNA)- and long non-coding RNA (lncRNA)-mediated mechanisms have been associated with epigenetic changes in prostate cancer. This review discusses the current evidence-based knowledge of the role of the phenotypic transitions and novel molecular determinants (non-coding RNAs) as contributors to the emergence of therapeutic resistance and metastasis and their integrated predictive value in prostate cancer progression to advanced disease.

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“…Existing compounds that can inhibit these clinically-validated targets may help to address this unmet need. Doxazosin (DOXA) is a quinazoline-based alpha 1-adrenergic receptor (A1AR) antagonist and is a widely-available drug used to treat benign prostate hyperplasia (BPH) and hypertension [ 19 ]. For the first time, we report the antitumor efficacy of DOXA in TNBC and explore its potential as a drug repurposing candidate.…”

Section: Introductionmentioning

confidence: 99%

Suppression of TNBC metastasis by doxazosin, a novel dual inhibitor of c-MET/EGFR

Kim,

Park,

Park

et al. 2023

J Exp Clin Cancer Res

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Background Triple-negative breast cancer (TNBC) is characterized by aggressive growth and a high propensity for recurrence and metastasis. Simultaneous overexpression of c-MET and EGFR in TNBC is associated with worse clinicopathological features and unfavorable outcomes. Although the development of new c-MET inhibitors and the emergence of 3rd-generation EGFR inhibitors represent promising treatment options, the high costs involved limit the accessibility of these drugs. In the present study, we sought to investigate the therapeutic potential of doxazosin (DOXA), a generic drug for benign prostate hyperplasia, in targeting TNBC. Methods The effect of DOXA on TNBC cell lines in vitro was evaluated in terms of cell viability, apoptosis, c-MET/EGFR signaling pathway, molecular docking studies and impact on cancer stem cell (CSC)-like properties. An in vivo metastatic model with CSCs was used to evaluate the efficacy of DOXA. Results DOXA exhibits notable anti-proliferative effects on TNBC cells by inducing apoptosis via caspase activation. Molecular docking studies revealed the direct interaction of DOXA with the tyrosine kinase domains of c-MET and EGFR. Consequently, DOXA disrupts important survival pathways including AKT, MEK/ERK, and JAK/STAT3, while suppressing CSC-like characteristics including CD44high/CD24low subpopulations, aldehyde dehydrogenase 1 (ALDH1) activity and formation of mammospheres. DOXA administration was found to suppress tumor growth, intra- and peri-tumoral angiogenesis and distant metastasis in an orthotopic allograft model with CSC-enriched populations. Furthermore, no toxic effects of DOXA were observed in hepatic or renal function. Conclusions Our findings highlight the potential of DOXA as a therapeutic option for metastatic TNBC, warranting further investigation.

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Repurposing of α1-Adrenoceptor Antagonists: Impact in Renal Cancer

Cited by 7 publications

References 45 publications

Quinazoline Derivatives as Potential Therapeutic Agents in Urinary Bladder Cancer Therapy

Quinazoline Derivatives as Potential Therapeutic Agents in Urinary Bladder Cancer Therapy

Non-Coding RNAs Set a New Phenotypic Frontier in Prostate Cancer Metastasis and Resistance

Suppression of TNBC metastasis by doxazosin, a novel dual inhibitor of c-MET/EGFR

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