Beyond the boundaries of cardiology: Still untapped anticancer properties of the cardiovascular system-related drugs.

Cardiovascular disorders and cancer are the most common chronic diseases, frequently coexistent and interdependent. Based on their common etiology and molecular background, the hypothesis on the potential anti-cancer activity of cardiological drugs appeared, mainly in response to the necessity of increasing the efficacy of existing oncological treatment schemes. In fact, cancer is known to induce the profound malfunction of typical cardiovascular-regulating systems, including the renin-angiotensin system, sympathetic nervous system and coagulation cascade. Therefore, in this review we have analyzed the available preclinical and clinical data on the repurposing potential of the following classes of cardiology drugs: angiotensin converting-enzyme inhibitors, angiotensin receptor blockers, beta blockers, statins and heparins. All of them have been shown to attenuate cancer development: the renin-angiotensin system inhibitors primarily by reducing inflammation, angiogenesis and immunosuppression, beta blockers by repressing migration and metastasis, heparins by decreasing metastasis and statins by influencing cell growth, apoptosis, migration and angiogenesis. We also have discussed the specific mechanisms of anticancer action for each group and then suggestions on their potential clinical use have been presented. Nonetheless, the establishment of strong indications for repurposing procedure, both individually and collectively, is unfeasible at the moment due to insufficient clinical data and therefore further investigations in this context are necessary and encouraged.

Can cardiovascular drugs support cancer treatment? The rationale for drug repurposing.

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), ß-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.

Synthesis, in vitro and in silico evaluation of novel trans-stilbene analogues as potential COX-2 inhibitors.

25 new trans-stilbene and trans-stilbazole derivatives were investigated using in vitro and in silico techniques. The selectivity and potency of the compounds were assessed using commercial ELISA test. The obtained results were incorporated into 2D QSAR assay. The most promising compound 4-nitro-3',4',5'-trihydroxy-trans-stilbene (N1) was synthetized and its potency and selectivity were confirmed. N1 was classified as preferential COX-2 inhibitor. Its ability to inhibit COX-2 in MCF-7 cell line was established and its cytotoxicity by MTT test was assessed. The compound was more cytotoxic than celecoxib within studied concentration range. Finally, the investigated trans-stilbene was docked into COX-1 and COX-2 active sites using "CDOCKER" protocol.

Unknown face of known drugs - what else can we expect from angiotensin converting enzyme inhibitors?

The renin-angiotensin system (RAS) is one of important systems among homeostatic mechanisms that control the function of cardiovascular, renal and adrenal systems. As RAS has a very complex nature, it has been also found as related to the control of cell migration and apoptosis. Angiotensin-converting enzyme inhibitors (ACEI) are drugs most commonly used in the modulation of RAS activity. ACEI have been extensively described as effective in the treatment of hypertension among adults, but also as drugs delaying progression in diabetic nephropathy and reducing mortality in left ventricular dysfunction and congestive heart failure. What is less obvious, ACEI are also widely used in pediatric nephrology and cardiology. Moreover, there are more and more reports showing evidence that ACEI can be beneficial in the treatment of many other diseases and the pleiotropic activity of ACEI is mainly based on their antioxidant properties. In this paper we focus on the less obvious possibilities of the clinical use of ACEI in neurological or oncological patients, discuss the role of ACE gene polymorphism and show the perspectives of potentially new applications of ACEI in contemporary pharmacotherapy.

COX-2 inhibitors: a novel strategy in the management of breast cancer.

Cyclooxygenase-2 (COX-2) inhibitors are common anti-inflammatory drugs with pleiotropic, endogenous actions that could be useful in the management of breast cancer. Here, we provide a complete understanding of the biochemistry of COX-2 and discuss the various molecular mechanisms behind its increased expression in breast cancer. We also analyze the possible mechanisms responsible for the anticancer effect of COX-2 inhibitors and provide an overview of the available preclinical and clinical data on the use of COX-2 inhibitors in breast cancer. Finally, we describe a mathematical model of the relation between the structure and biological potency of promising new COX-2 inhibitors (trans-stilbenes) using a 2D quantitative structure-activity relationship (QSAR) technique.

Chemistry and pharmacology of Angiotensin-converting enzyme inhibitors.

The renin-angiotensin system has been established as an attractive target for pharmacological intervention since the discovery of first angiotensin-converting enzyme inhibitors (ACE-Is). In fact, these drugs are primarily used in the management of cardiovascular system-related diseases and renal insufficiency. Their mechanism of action involves the adjustment of balance between vasoconstrictive, hypertrophic and salt/water-retentive angiotensin II and vasodilatory and natriuretic bradykinin by the inhibition of angiotensin II biosynthesis and bradykinin degradation. Currently there are thirteen family members approved for use in humans. They differ in structure, chemistry and pharmacokinetic and pharmacodynamic properties yet they display a similar pharmacologic and toxicologic profile. All of them are effective in the treatment of hypertension as well as in cardiac insufficiency or diabetic nephropathy. Although they are generally well-tolerated several serious side-effects including life-threatening angioedema, renal failure and persistent dry cough could occur during the administration of ACE-Is, which may require the cessation of therapy. Furthermore, to provide maximum safety and efficiency of ACE-Is-based therapy, the knowledge of the related drug interactions and chronokinetics seems to be an absolute requirement. Here we discuss the above-mentioned issues regarding the pharmaceutical and chemical properties of the commercially- used ACE-Is.

The mutagenicity analysis of imidapril hydrochloride and its degradant, diketopiperazine derivative, nitrosation mixtures by in vitro Ames test with two strains of Salmonella typhimurium.

AIM: The evaluation of mutagenic properties of imidapril hydrochloride (IMD) and its degradation impurity, diketopiperazine derivative (DKP), nitrosation mixtures was conducted in order to analyze the carcinogenic risk of IMD long-term treatment in patients. In this study an in vitro Ames test with Salmonella enterica serovar Typhimurium TA 98 and TA 100 strains was used. BACKGROUND: IMD and DKP contain nitrogen atoms, which makes them theoretically vulnerable to in vivo nitrosation with the production of N-nitroso compounds (NOC). NOC, in turn, are known animal mutagens indicating that their endogenous production from nitrosable drugs constitutes a carcinogenic hazard. MATERIALS AND METHODS: Pure IMD sample was exposed to forced degradation conditions of increased temperature and dry air in order to achieve a DKP sample. Both samples were then treated with a nitrosating agent and the obtained nitrosation mixtures were subjected to mutagenicity analysis by the Ames test with S. typhimurium TA 98 and TA 100 strains in the presence and absence of metabolic activation system (S9 mix) using a commercial Ames MPF 98/100 microplate format mutagenicity assay kit. RESULTS: None of the six concentrations of the investigated nitrosation mixtures exhibited any mutagenic potential in both S. typhimurium strains. The addition of S9 mix did not alter the non-mutagenic properties of the studied compounds. CONCLUSIONS: The nitrite treatment of both studied compounds has no impact on their mutagenic properties under the conditions of the present studies. Hence, IMD and DKP nitrosation mixtures are classified as non-mutagens in this test.

How to design a potent, specific, and stable angiotensin-converting enzyme inhibitor.

Angiotensin-converting enzyme inhibitors (ACE-Is) are a valuable class of antihypertensive drugs used in the treatment of cardiovascular system-related diseases. Hence, constant research into, and the development of, such compounds remain within the priorities of modern medical sciences. In this respect, a thorough understanding of their chemistry and biology is an important aspect of drug design; therefore, we present here available data on the pharmaceutical properties of ACE-Is. We also review the structural and biochemical features of the molecular target of ACE-Is and demonstrate several known enzyme-inhibitor complexes. Finally, we attempt to create a mathematical model describing the relation between the potency and/or stability of ACE-Is and their structural characteristics using quantitative structure-activity relation (QSAR), and quantitative structure-property relation (QSPR) techniques.

[Molecular fundamentals of drug interactions in the therapy of colorectal cancer]. / Molekularne podstawy interakcji miedzylekowych w terapii nowotworów jelita grubego

Rapid advances in the field of chemotherapy have resulted in the introduction of numerous antineoplastic drugs into clinical practice, which increased the efficiency of patient management. Also the prevalent use of combination treatment based on drug action synergy contributed to the improved clinical effect associated with cytotoxic drug administration. It seems, however, obvious that the multidirectional pharmacotherapy in oncology requires a thorough knowledge of drugs' pharmaceutical behavior in order to maximize their collective action and prevent the occurrence of unintended drug interactions that could potentially impair treatment effectiveness. In fact, drug interactions constitute a serious problem for current oncology primarily resulting from a narrow therapeutic index specific for the majority of anticancer drugs. This, in turn, indicates that even slight deviations of their pharmacokinetics could cause significant clinical consequences, manifested by alteration of the toxicological profile or reduction of therapeutic efficiency. Hence, the investigation of molecular aspects underlying the mechanisms of various drug interactions seems to be essential for proper and safe patient management. The present article is devoted to the extensive subject of drug interactions occurring in the therapy of colorectal cancer. It presents the available literature data on both positive and negative effects of interactions and it discusses their mechanisms complying with their classification into pharmacokinetic and pharmacodynamic ones.

Is there any association between imidapril hydrochloride stability profile under dry air conditions and cancer initiation?

Stability study for imidapril hydrochloride (IMD) was performed under stress conditions of increased temperature (T=373 K) and decreased relative air humidity (RH=0%) in order to obtain and identify its degradation product. The degradation sample stored for 15 days under the above environmental conditions was analyzed by LC-MS technique and it was found that the only degradation impurity formed in the course of the investigated drug degradation was IMD diketopiperazine derivative (DKP) which was produced by dehydration and intramolecular cyclization. The kinetics of its formation was analyzed by a revalidated RP-HPLC method and the kinetic model of this reaction was established. It was concluded that the DKP formation follows Prout-Tompkins kinetics with the rate constant k±Δk=2.034±0.157×10(-6) [s(-1)]. The obtained degradation impurity was further assessed with respect to its mutagenic potential using commercial Ames MPF 98/100 microplate format mutagenicity assay kit equipped with Salmonella typhimurium strains TA 98 and TA 100. Both strains were exposed to six concentrations (in a range of 0.16-5.0mg/mL) of DKP in the presence and absence of metabolic activation system. No mutagenic effect was observed confirming that the presence of DKP in IMD final dosage form has no impact on cancer initiation.

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

The role of the renin-angiotensin system (RAS) in the development of various malignancies has recently been extensively examined and, since it has been shown to significantly influence many aspect of cancer initiation and progression, the idea of RAS-targeted anticancer therapy has arisen. This article reviews the mechanisms underlying RAS-induced physiological and pathological responses related to cancer biology, including tumor growth, cell proliferation, apoptosis, angiogenesis, inflammation, and protein degradation, emphasizing the associated cellular transduction schemes activated by main RAS effectors. Also the dual nature of RAS-dependent effects, resulting from its complex physiology has been commented. Finally, based on the available data from clinical trials and experimental studies, the possibilities of the introduction of RAS-modulating drugs into standard clinical practice in oncology have been discussed with the focus on both, positive and negative effects associated with the administration of various classes of pharmaceuticals to cancer patients.

[Individualization of anticancer therapy; molecular targets of novel drugs in oncology]. / Indywidualizacja terapii przeciwnowotworowej; molekularne uwarunkowania mechanizmów dzialania nowoczesnych leków onkologicznych.

Deregulation of cellular signal transduction, caused by gene mutations, has been recognized as a basic factor of cancer initiation, promotion and progression. Thus, the ability to control the activity of overstimulated signal molecules by the use of appropriate inhibitors became the idea of targeted cancer therapy, which has provided an effective tool to normalize the molecular disorders in malignant cells and to treat certain types of cancer. The molecularly targeted drugs are divided into two major pharmaceutical classes: monoclonal antibodies and small-molecule kinase inhibitors. This review presents a summary of their characteristics, analyzing their chemical structures, specified molecular targets, mechanisms of action and indications for use. Also the molecules subjected to preclinical trials or phase I, II and III clinical trials evaluating their efficiency and safety are presented. Moreover, the article discusses further perspectives for development of targeted therapies focusing on three major directions: systematic searching and discovery of new targets that are oncogenic drivers, improving the pharmacological properties of currently known drugs, and developing strategies to overcome drug resistance. Finally, the role of proper pharmacodiagnostics as a key to rational anticancer therapy has been emphasized since the verification of reliable predictive biomarkers is a basis of individualized medicine in oncology. 

Assessing circadian rhythms in propofol PK and PD during prolonged infusion in ICU patients.

This study evaluates possible circadian rhythms during prolonged propofol infusion in patients in the intensive care unit. Eleven patients were sedated with a constant propofol infusion. The blood samples for the propofol assay were collected every hour during the second day, the third day, and after the termination of the propofol infusion. Values of electroencephalographic bispectral index (BIS), arterial blood pressure, heart rate, blood oxygen saturation and body temperature were recorded every hour at the blood collection time points. A two-compartment model was used to describe propofol pharmacokinetics. Typical values of the central and peripheral volume of distribution and inter-compartmental clearance were V(C) = 27.7 l, V(T) = 801 l, and CL(D) = 2.73 l/min. The systolic blood pressure (SBP) was found to influence the propofol metabolic clearance according to Cl (l/min) = 2.65 x (1-0.00714 x (SBP-135)). There was no significant circadian rhythm detected with respect to propofol pharmacokinetics. The BIS score was assessed as a direct effect model with EC(50) equal 1.98 mg/l. There was no significant circadian rhythm detected within the BIS scores. We concluded that the light-dark cycle did not influence propofol pharmacokinetics and pharmacodynamics in intensive care units patients. The lack of night-day differences was also noted for systolic blood pressure, diastolic blood pressure and blood oxygenation. Circadian rhythms were detected for heart rate and body temperature, however they were severely disturbed from the pattern of healthy patients.