Multitargeted polypharmacotherapy for cancer treatment. theoretical concepts and proposals.

INTRODUCTION: The pharmacological treatment of cancer has evolved from cytotoxic to molecular targeted therapy. The median survival gains of 124 drugs approved by the FDA from 2003 to 2021 is 2.8 months. Targeted therapy is based on the somatic mutation theory, which has some paradoxes and limitations. While efforts of targeted therapy must continue, we must study newer approaches that could advance therapy and affordability for patients. AREAS COVERED: This work briefly overviews how cancer therapy has evolved from cytotoxic chemotherapy to current molecular-targeted therapy. The limitations of the one-target, one-drug approach considering cancer as a robust system and the basis for multitargeting approach with polypharmacotherapy using repurposing drugs. EXPERT OPINION: Multitargeted polypharmacotherapy for cancer with repurposed drugs should be systematically investigated in preclinical and clinical studies. Remarkably, most of these proposed drugs already have a long history in the clinical setting, and their safety is known. In principle, the risk of their simultaneous administration should not be greater than that of a first-in-human phase I study as long as the protocol is developed with strict vigilance to detect early possible side effects from their potential interactions. Research on cancer therapy should go beyond the prevailing paradigm targeted therapy.

Effects of the tetravanadate [V4O12]4- anion on the structural, magnetic, and biological properties of copper/phenanthroline complexes.

The aim to access linked tetravanadate [V4O12]4- anion with mixed copper(II) complexes, using α-amino acids and phenanthroline-derived ligands, resulted in the formation of four copper(II) complexes [Cu(dmb)(Gly)(OH2)]2[Cu(dmb)(Gly)]2[V4O12]·9H2O (1) [Cu(dmb)(Lys)]2[V4O12]·8H2O (2), [Cu(dmp)2][V4O12]·C2H5OH·11H2O (3), and [Cu(dmp)(Gly)Cl]·2H2O (4), where dmb = 4,4'-dimethioxy-2,2'-bipyridine; Gly = glycine; Lys = lysine; and dmp = 2,9-dimethyl-1,10-phenanthroline. The [V4O12]4- anion is functionalized with mixed copper(II) units in 1 and 2; while in 3, it acts as a counterion of two [Cu(dmp)]2+ units. Compound 4 crystallized as a unit that did not incorporate the vanadium cluster. All compounds present magnetic couplings arising from Cu⋯O/Cu⋯Cu bridges. Stability studies of water-soluble 3 and 4 by UV-Vis spectroscopy in cell culture medium confirmed the robustness of 3, while 4 appears to undergo ligand scrambling over time, resulting partially in the stable species [Cu(dmp)2]+ that was also identified by electrospray ionization mass spectrometry at m/z = 479. The in vitro cytotoxicity activity of 3 and 4 was determined in six cancer cell lines; the healthy cell line COS-7 was also included for comparative purposes. MCF-7 cells were more sensitive to compound 3 with an IC50 value of 12 ± 1.2 nmol. The tested compounds did not show lipid peroxidation in the TBARS assay, ruling out a mechanism of action via reactive oxygen species formation. Both compounds inhibited cell migration at 5 µM in wound-healing assays using MCF-7, PC-3, and SKLU-1 cell lines, opening a new window to study the anti-metastatic effect of mixed vanadium-copper(II) systems.

Selection of clinically relevant drug concentrations for in vitro studies of candidates drugs for cancer repurposing: a proposal.

Drug repurposing of widely prescribed patent-off and cheap drugs may provide affordable drugs for cancer treatment. Nevertheless, many preclinical studies of cancer drug repurposing candidates use in vitro drug concentrations too high to have clinical relevance. Hence, preclinical studies must use clinically achievable drug concentrations. In this work, several FDA-approved cancer drugs are analyzed regarding the correlation between the drug inhibitory concentrations 50% (IC50) tested in cancer cell lines and their corresponding peak serum concentration (Cmax) and area under the curve (AUC) reported in clinical studies of these drugs. We found that for most targeted cancer drugs, the AUC and not the Cmax is closest to the IC50; therefore, we suggest that the initial testing of candidate drugs for repurposing could select the AUC pharmacokinetic parameter and not the Cmax as the translated drug concentration for in vitro testing. Nevertheless, this is a suggestion only as experimental evidence does not exist to prove this concept. Studies on this issue are required to advance in cancer drug repurposing.

PaSTe. Blockade of the Lipid Phenotype of Prostate Cancer as Metabolic Therapy: A Theoretical Proposal.

BACKGROUND: Prostate cancer is the most frequently diagnosed malignancy in 112 countries and is the leading cause of death in eighteen. In addition to continuing research on prevention and early diagnosis, improving treatments and making them more affordable is imperative. In this sense, the therapeutic repurposing of low-cost and widely available drugs could reduce global mortality from this disease. The malignant metabolic phenotype is becoming increasingly important due to its therapeutic implications. Cancer generally is characterized by hyperactivation of glycolysis, glutaminolysis, and fatty acid synthesis. However, prostate cancer is particularly lipidic; it exhibits increased activity in the pathways for synthesizing fatty acids, cholesterol, and fatty acid oxidation (FAO). OBJECTIVE: Based on a literature review, we propose the PaSTe regimen (Pantoprazole, Simvastatin, Trimetazidine) as a metabolic therapy for prostate cancer. Pantoprazole and simvastatin inhibit the enzymes fatty acid synthase (FASN) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), therefore, blocking the synthesis of fatty acids and cholesterol, respectively. In contrast, trimetazidine inhibits the enzyme 3-b-Ketoacyl-CoA thiolase (3-KAT), an enzyme that catalyzes the oxidation of fatty acids (FAO). It is known that the pharmacological or genetic depletion of any of these enzymes has antitumor effects in prostatic cancer. RESULTS: Based on this information, we hypothesize that the PaSTe regimen will have increased antitumor effects and may impede the metabolic reprogramming shift. Existing knowledge shows that enzyme inhibition occurs at molar concentrations achieved in plasma at standard doses of these drugs. CONCLUSION: We conclude that this regimen deserves to be preclinically evaluated because of its clinical potential for the treatment of prostate cancer.

Does Therapeutic Repurposing in Cancer Meet the Expectations of Having Drugs at a Lower Price?

Therapeutic repurposing emerged as an alternative to the traditional drug discovery and development model (DDD) of new molecular entities (NMEs). It was anticipated that by being faster, safer, and cheaper, the development would result in lower-cost drugs. As defined in this work, a repurposed cancer drug is one approved by a health regulatory authority against a non-cancer indication that then gains new approval for cancer. With this definition, only three drugs are repurposed for cancer: Bacillus Calmette-Guerin (BCG) vaccine (superficial bladder cancer, thalidomide [multiple myeloma], and propranolol [infantile hemangioma]). Each of these has a different history regarding price and affordability, and it is not yet possible to generalize the impact of drug repurposing on the final price to the patient. However, the development, including the price, does not differ significantly from an NME. For the end consumer, the product's price is unrelated to whether it followed the classical development or repurposing. Economic constraints for clinical development, and drug prescription biases for repurposing drugs, are barriers yet to be overcome. The affordability of cancer drugs is a complex issue that varies from country to country. Many alternatives for having affordable drugs have been put forward, however these measures have thus far failed and are, at best, palliative. There are no immediate solutions to the problem of access to cancer drugs. It is necessary to critically analyze the impact of the current drug development model and be creative in implementing new models that genuinely benefit society.

Phytochemical Study of Eryngium cymosum F. Delaroche and the Inhibitory Capacity of Its Main Compounds on Two Glucose-Producing Pathway Enzymes.

One undescribed acylated flavonol glucoside and five known compounds were isolated from the aerial parts of Eryngium cymosum F. Delaroche, a plant that is used in traditional Mexican medicine to treat type 2 diabetes. The chemical structures of the isolated compounds were elucidated using a variety of spectroscopic techniques, including 1D and 2D nuclear magnetic resonance (NMR) and mass spectrometry (MS). Chlorogenic acid (1), rosmarinic acid (2), caffeic acid (3), protocatechuic acid (4), kaempferol-3-O-(2,6-di-O-trans-ρ-coumaryl)-ß-d-glucopyranoside (5), and the new acylated flavonol glucoside quercetin-3-O-(2,6-di-O-trans-ρ-coumaryl)-ß-d-glucopyranoside (6) were isolated. This is the first report on the natural occurrence of quercetin-3-O-(2,6-di-O-trans-ρ-coumaryl)-ß-D-glucopyranoside (6). In addition, according to the HPLC profile obtained for the water extract (WE), chlorogenic acid (1) and rosmarinic acid (2) were identified as the main compounds, while kaempferol-3-O-(2,6-di-O-trans-ρ-coumaryl)-ß-d-glucopyranoside (5) were the main compound in the butanolic extract. We demonstrate the important role of compound 5 over the inhibition of G6Pase and FBPase. The isolated compounds may play an important role in the hypoglycemic effect of the extract and may act in a synergic way, but more experiments are needed to corroborate these findings.

Progress in Metabolic Studies of Gastric Cancer and Therapeutic Implications.

BACKGROUND: Worldwide, gastric cancer is ranked the fifth malignancy in incidence and the third malignancy in mortality. Gastric cancer causes an altered metabolism that can be therapeutically exploited. OBJECTIVE: The objective of this study is to provide an overview of the significant metabolic alterations caused by gastric cancer and propose a blockade. METHODS: A comprehensive and up-to-date review of descriptive and experimental publications on the metabolic alterations caused by gastric cancer and their blockade. This is not a systematic review. RESULTS: Gastric cancer causes high rates of glycolysis and glutaminolysis. There are increased rates of de novo fatty acid synthesis and cholesterol synthesis. Moreover, gastric cancer causes high rates of lipid turnover via fatty acid ß-oxidation. Preclinical data indicate that the individual blockade of these pathways via enzyme targeting leads to antitumor effects in vitro and in vivo. Nevertheless, there is no data on the simultaneous blockade of these five pathways, which is critical as tumors show metabolic flexibility in response to the availability of nutrients. This means tumors may activate alternate routes when one or more are inhibited. We hypothesize there is a need to simultaneously block them to avoid or decrease the metabolic flexibility that may lead to treatment resistance. CONCLUSION: There is a need to explore the preclinical efficacy and feasibility of combined metabolic therapy targeting the pathways of glucose, glutamine, fatty acid synthesis, cholesterol synthesis, and fatty acid oxidation. This may have therapeutical implications because we have clinically available drugs that target these pathways in gastric cancer.

BAPST. A Combo of Common Use Drugs as Metabolic Therapy for Cancer: A Theoretical Proposal.

Cancer therapy advances have yet to impact global cancer mortality. One of the factors limiting mortality burden reduction is the high cost of cancer drugs. Cancer drug repurposing has already failed to meet expectations in terms of drug affordability. The three FDA-approved cancer drugs developed under repurposing: all-trans-retinoic acid, arsenic trioxide, and thalidomide do not differ in price from other drugs developed under the classical model. Though additional factors affect the whole process from inception to commercialization, the repurposing of widely used, commercially available, and cheap drugs may help. This work reviews the concept of the malignant metabolic phenotype and its exploitation by simultaneously blocking key metabolic processes altered in cancer. We elaborate on a combination called BAPST, which stands for the following drugs and pathways they inhibit: Benserazide (glycolysis), Apomorphine (glutaminolysis), Pantoprazole (Fatty-acid synthesis), Simvastatin (mevalonate pathway), and Trimetazidine (Fatty-acid oxidation). Their respective primary indications are: • Parkinson's disease (benserazide and apomorphine). • Peptic ulcer disease (pantoprazole). • Hypercholesterolemia (simvastatin). • Ischemic heart disease (trimetazidine). When used for their primary indication, the literature review on each of these drugs shows that they have a good safety profile and lack predicted pharmacokinetic interaction among them. Based on that, we propose that the BAPST regimen merits preclinical testing.

Chronic hypoglycemic effect and phytochemical composition of Smilax moranensis roots

ABSTRACT Smilax moranensis M.Martens & Galeotti, Smilacaceae, root is a medicinal plant used among the Chatinos in Oaxaca, Mexico, to control type 2 diabetes. The objectives of the study were to isolate the bioactive compounds from the roots of Smilax and evaluate the chronic hypoglycemic effect of the ethanol-water extract. The main compounds were isolated from the methanolic extract via conventional phytochemical methods. The dried roots of S. moranensis were extracted with methanol and chromatographed on Sephadex LH 20. Fractions were chromatographed and purified on a silica gel chromatography column. The ethanol-water extract was orally administered to hyperglycemic rats for a period of 42 days, and glucose, glycated hemoglobin (HbA1c), and triacylglycerides were measured. Moreover, very-low-density lipoprotein was calculated. During the chemical investigation, three compounds were isolated and characterized, namely, 3-O-caffeoyl-quinic acid, 5-O-caffeoyl-quinic acid and trans-resveratrol, using various spectroscopic techniques. Animal experiments confirmed that the plant extract could control both the glucose and HbA1c levels. In conclusion, this study confirms that the roots of S. moranensis have hypoglycemic properties and suggests that the isolated compounds are potentially involved in this effect.

Cytotoxic Activity and Structure-Activity Relationship of Triazole-Containing Bis(Aryl Ether) Macrocycles.

Cancer continues to be a worldwide health problem. Certain macrocyclic molecules have become attractive therapeutic alternatives for this disease because of their efficacy and, frequently, their novel mechanisms of action. Herein, we report the synthesis of a series of 20-, 21-, and 22-membered macrocycles containing triazole and bis(aryl ether) moieties. The compounds were prepared by a multicomponent approach from readily available commercial substrates. Notably, some of the compounds displayed interesting cytotoxicity against cancer (PC-3) and breast (MCF-7) cell lines, especially those bearing an aliphatic or a trifluoromethyl substituent on the N-phenyl moiety (IC50 <13 µm). Additionally, some of the compounds were able to induce apoptosis relative to the solvent control; in particular, (Z)-N-cyclohexyl-7-oxo-6-[4-(trifluoromethyl)phenyl]-11 H-3,10-dioxa-6-aza-1(4,1)-triazola-4(1,3),9(1,4)-dibenzenacyclotridecaphane-5-carboxamide (12 f) was the most potent in this regard (22.7 % of apoptosis).

Mild C(sp3)-H functionalization of dihydrosanguinarine and dihydrochelerythrine for development of highly cytotoxic derivatives.

A series of C(6)-substituted dihydrobenzo[c]phenanthridines were synthesized by mild copper-catalyzed C(sp3)-H functionalization of dihydrosanguinarine (2) and dihydrochelerythrine (3) with certain nucleophiles selected to enhance cytotoxicity against human breast, colorectal, and prostate cancer cell lines. We also investigated the cytotoxicity of our previously reported C(6)-functionalized N-methyl-5,6-dihydrobenzo[c]phenanthridines 1a-1e to perform structure-activity relationship (SAR) studies. Among the target compounds, five ß-aminomalonates (1a, 1b, 2a, 2b, and 3b), one α-aminophosphonate (2c), and one nitroalkyl derivative (2h) exhibited half maximal inhibitory concentration (IC50) values in the range of 0.6-8.2 µM. Derivatives 1b, 2b and 2h showed the lowest IC50 values, with 2b being the most potent with values comparable to those of the positive control doxorubicin. On the basis of their IC50 values, derivatives 1a, 1b, 2a, 2b, 2h, and 3b were selected to evaluate the apoptotic PC-3 cell death at 10 µM by flow cytometry using propidium iodide and fluorescein isothiocyanate-conjugated Annexin V dual staining. The results indicated that the cytotoxic activity of the tested compounds in PC-3 cells is due to the induction of apoptosis, with 1a and 2h being the most active (55% of early apoptosis induction). Our preliminary SAR study showed that the incorporation of specific malonic esters, dialkyl phosphites and nitro alkanes on scaffolds 1-3 significantly enhanced their cytotoxic properties. Moreover, it appears that the electron donating 7,8-methylenedioxy group allowed derivatives of 2 to exhibit higher cytotoxicity than derivatives of 1 and 3. The present results suggest that derivatives 2b and 2h may be considered as potential lead compounds for the development of new anticancer agents.