Beta-blocker adjunct therapy as a prospective anti-metastatic with cardio-oncologic regulation.

The prevailing treatment stratagem in cancer therapy still challenges the dilemma of a probable metastatic spread following an initial diagnosis. Including an anti-metastatic agent demands a significant focus to overrule the incidence of treatment failures. Adrenergic stimulation underlying the metastatic spread paved the way for beta blockers as a breakthrough in repurposing as an anti-metastatic agent. However, the current treatment approach fails to fully harness the versatile potential of the drug in inhibiting probable metastasis. The beta blockers were seen to show a myriad of grip over the pro-metastatic and prognostic parameters of the patient. Novel interventions in immune therapy, onco-hypertension, surgery-induced stress, induction of apoptosis and angiogenesis inhibition have been used as evidence to interpret our objective of discussing the potential adjuvant role of the drug in the existing anti-cancer regimens. Adding weight to the relative incidence of onco-hypertension as an unavoidable side effect from chemotherapy, the slot for an anti-hypertensive agent is necessitated, and we try to suggest beta-blockers to fill this position. However, pointing out the paucity in the clinical study, we aim to review the current status of beta blockers under this interest to state how the drug should be included as a drug of choice in every patient undergoing cancer treatment.

Exploring the effects of vasoactive constituents in large cardamom: implications for the anti-hypertensive effect via eNOS coupling pathway - an in-vitro study in rat endothelial cells.

Endothelial dysfunction, linked to reduced eNOS expression and nitric oxide (NO) availability, contributes to cardiovascular diseases (CVDs). Large cardamom exhibits antihypertensive effects by augmenting NO levels and antioxidant activity. To decipher its mechanisms, selected constituents were docked with eNOS-associated target genes such as GTP cyclohydrolase I (GTPCH-1) and (dihydrofolate reductase [DHFR]). Endothelial damage induced by L-NAME and fructose was countered by assessing nitric oxide metabolites (NOx), tetrahydrobipterin (BH4 levels), GCH-I expression and super oxide dismutase (SOD) activity after constituent incubation. Cyanidin-3-O-glucoside and petunidin-3-O-glucoside notably restored impaired vascular markers in both models. These phytoconstituents are likely to activate GCH-BH4-eNOS pathways, upregulating SOD and NO expression, maintaining endothelial integrity. Large cardamom's antihypertensive effects may stem from these components, synergistically enhancing endothelial NO release via the eNOS pathway.

Heterocyclic and non-heterocyclic arena of monocarboxylate transporter inhibitors to battle tumorigenesis.

Monocarboxylate transporters (MCTs) have gained significant attention in cancer research due to their critical role in tumour metabolism. MCTs are legends for transporting lactate molecules in cancer cells, an oncometabolite and waste product of glycolysis, acting as an indispensable factor of tumour proliferation. Targeting MCTs with inhibitors has emerged as a promising strategy to combat tumorigenesis. This article summarizes the most recent research on MCT inhibitors in preventing carcinogenesis, covering both heterocyclic and non-heterocyclic compounds. Heterocyclic and non-heterocyclic compounds such as pteridine, pyrazole, indole, flavonoids, coumarin derivatives and cyanoacetic acid derivatives have been reported as potent MCT inhibitors. We examine the molecular underpinnings of MCTs in cancer metabolism, the design and synthesis of heterocyclic and non-heterocyclic MCT inhibitors, their impact on tumour cells and the microenvironment and their potential as therapeutic agents. Moreover, we explore the challenges associated with MCT inhibitor development and propose future directions for advancing this field. This write-up aims to provide researchers, scientists and clinicians with a comprehensive understanding of the heterocyclic and non-heterocyclic MCT inhibitors and their potential in combating tumorigenesis.

Imidazole-pyridine hybrids as potent anti-cancer agents.

In the current investigation, fifteen novel imidazole-pyridine-based molecules were synthesized and tested against cell lines of the lung (H1299) and colon (HCT116) adenocarcinomas by proliferation assay. The results demonstrated that compounds 5a, 5d, 5e, and 5f were the most active (IC50<30 µM). Based on recent literature and the current results, the glycogen synthase kinase-3ß (GSK-3ß) protein was investigated in-silico as a possible target. The molecular docking and QSAR revealed an excellent binding affinity of the selected imidazole-pyridine compounds to GSK-3ß. Notably, GSK-3ß protein levels were significantly upregulated in hepatocellular liver carcinoma (LIHCs) tissues and negatively affected patient prognosis. Consequently, the compounds were evaluated on liver cancer cell lines (HepG2, HUH-7, and PLC/PRF/5) by the MTT assay, and 5d showed the highest antitumor activity. This study offers new compounds with interesting biological activity on GSK-3ß as a target, exhibiting a potential therapeutic impact for hepatocellular carcinoma patients.

Design, Synthesis, and Anti-Breast Cancer Potential of Imidazole-Pyridine Hybrid Molecules In Vitro and Ehrlich Ascites Carcinoma Growth Inhibitory Activity Assessment In Vivo.

Breast cancer remains a challenging medical issue and is a high priority for biomedical research despite significant advancements in cancer research and therapy. The current study aims to determine the anticancer activity of a group of imidazole-pyridine-based scaffolds against a variety of breast cancer cell lines differing in their receptor expression (estrogen receptor (ER), progesterone receptor (PR), and HER-2). A series of 10 molecules (coded 5a-5j) were synthesized through multicomponent and alkylation reactions. FTIR, MS, 1H, and 13C NMR spectral analyses confirmed the structures and purity of the synthesized molecules. Subsequently, these molecules were tested for their ability to inhibit the viability of cell lines representing carcinoma of the breast, viz., MDA-MB-468 (ER-, PR-, and HER-), BT-474 (ER+, PR+, and HER+), T-47D (ER+, PR+, and HER-), and MCF-7 (ER+, PR+, and HER-) in vitro. Among these 10 molecules, 5a, 5c, 5d, and 5e exhibited better potency, as evidenced by IC50 < 50 µM at 24 h of treatment against BT-474 and MDA-MB-468 cell lines. However, except for 5d, the IC50 value is much higher than 50 µM when tested against T47D and MCF-7 cell lines at 24h. Extended treatment for 48 h reduced the effect of these molecules, as an increase in IC50 was observed. In mice, intraperitoneal administration of 5e retarded the Ehrlich ascites carcinoma (EAC) growth without causing any organ toxicity at the doses tested. In summary, we report the synthesis scheme and key structural requirements for a new series of imidazole-pyridine molecules for in vitro inhibition of the feasibility of breast cancer cells and in vivo inhibition of EAC tumors.

A computational investigation of thymidylate synthase inhibitors through a combined approach of 3D-QSAR and pharmacophore modelling.

Thymidylate synthase (TS) is a crucial target of cancer drug discovery and is mainly involved in the De novo synthesis of the DNA precursor thymine. In the present study, to generate reliable models and identify a few promising molecules, we combined QSAR modelling with the pharmacophore hypothesis-generating technique. Input molecules were clustered on their similarity, and a cluster of 74 molecules with a pyrimidine moiety was chosen as the set for 3D-QSAR and pharmacophore modelling. Atom-based and field-based 3D-QSAR models were generated and statistically validated with R2 > 0.90 and Q2 > 0.75. The common pharmacophore hypothesis(CPH) generation identified the best six-point model ADHRRR. Using these best models, a library of FDA-approved drugs was screened for activity and filtered via molecular docking, ADME profiling, and molecular dynamics simulations. The top ten promising TS-inhibiting candidates were identified, and their chemical features profitable for TS inhibitors were explored.Communicated by Ramaswamy H. Sarma.

In silico development of potential InhA inhibitors through 3D-QSAR analysis, virtual screening and molecular dynamics.

Tuberculosis is one of the most ancient infectious diseases known to mankind predating upper Paleolithic era. In the current scenario, treatment of drug resistance tuberculosis is the major challenge as the treatment options are limited, less efficient and more toxic. In our study we have developed an atom based 3D QSAR model, statistically validated sound with R2 > 0.90 and Q2 > 0.72 using reported direct inhibitors of InhA (2018-2022), validated by enzyme inhibition assay. The model was used to screen a library of 3958 molecules taken from Binding DB and candidates molecules with promising predicted activity value (pIC50) > 5) were selected for further analyzed screening by using molecular docking, ADME profiling and molecular dynamic simulations. The lead molecule, ZINC11536150 exhibited good docking score (glideXP = -11.634 kcal/mol) compared to standard triclosan (glideXP = -7.129 kcal/mol kcal/mol) and through molecular dynamics study it was observed that the 2nv6-complex of ZINC11536150 with Mycobacterium tuberculosis InhA (PDB entry: 2NV6) complex remained stable throughout the entire simulation time of 100 ns.Communicated by Ramaswamy H. Sarma.

The Promising Role of Natural Exosomal Nanoparticles in Cancer Chemoimmunotherapy.

Exosomal nanoparticles are cell-derived nano-sized vesicles in the size range of 30-150nm formed by the inward infolding of the cell membrane. They are encased in a lipid bilayer membrane and contain various proteins and nucleic acids according to the characteristics of their parent cell. They are involved in intercellular communication. Their specific structural and inherent properties are helpful in therapeutics and as biomarkers in diagnostics. Since they are biomimetic, these small-sized nanoparticles pose many advantages if used as a drug carrier vehicle. In cancer, the exosomal nanoparticles have both stimulatory and inhibitory activity towards immune responses; hence, they are used in immunotherapy. They can also carry chemotherapeutic agents to the target site minimizing their targetability concerns. Chemoimmunotherapy (CIT) is a synergistic approach in which chemotherapy and immunotherapy are utilized to benefit each other. Exosomal nanoparticles (NPs) are essential in delivering CIT agents into tumor tissues. Most advanced studies in CIT take place in the stimulator of interferon genes (STING) signaling pathway, where the STING activation supported by chemotherapy-induced an increase in immune surveillance through the help of exosomal NPs. Dendritic cell(DC) derived exosomes, as well as Mesenchymal stem cells (MSC), are abundantly used in immunotherapy, and hence their support can be used in chemoimmunotherapy (CIT) for multifaceted benefits.

Network analysis and ligand-based pharmacophore modeling for discovery of small molecule against glioblastoma multiforme.

Aim: This study uses network pharmacology to design a c-Src inhibitor followed by pharmacophore modeling to combat glioblastoma multiforme. These in silico approaches are suitable for designing and developing new molecules of interest. Materials & methods: The authors performed virtual screening, pharmacophore analysis and validation of results using various in silico tools and reliable data from different types of literature and databases. Results: The in silico pipeline the authors followed produced reliable chemical information to combat glioblastoma. The authors identified a chemical template against the c-Src protein, which was validated statistically and computationally. Conclusion: The authors have successfully identified a chemical template against c-Src, which will be developed into a promising inhibitor in future studies.

From Warburg effect to Reverse Warburg effect; the new horizons of anti-cancer therapy.

An old ideology of killing the cancer cells by starving them is the underlying concept of the Warburg effect. It is the process of aerobic glycolysis exhibited by the cancer cells irrespective of anaerobic glycolysis or mitochondrial oxidative phosphorylation following by their healthy counterparts. Dr Otto Heinrich Warburg proposed this abnormal metabolic behaviour of tumour cells in 1920. This phenomenon illustrates the metabolic switching in tumour cells from oxidative phosphorylation to aerobic glycolysis triggered by an injury to the mitochondrial respiration. A modernised perspective of the Warburg hypothesis termed the Reverse Warburg effect introduced in 2009, with a two-compartment model describing the metabolic symbiosis between cancer cells and its neighbouring stromal cells or cancer-associated fibroblasts. This theory is elucidating the aerobic glycolysis occurring in cancer-associated fibroblasts which leads to the generation and deposition of the lactate in tumour microenvironment along with its significance. The transportation of lactate to and from the cancer cell and extracellular space is facilitated by the lactate transporters called monocarboxylate transporters. This lactate generated irrespective of the hypoxic or aerobic conditions acts as a primary metabolic fuel for the cancer cells. Besides, it will create a tumour microenvironment that is favouring the progression and metastasis of malignancy through several means. Overall, the lactate produced through this metabolic reprogramming is supporting and worsening the conditions of cancer. The concept of the Reverse Warburg effect proposes a new anti-cancer treatment modality by preventing the generation and transport of lactate through the inhibition of monocarboxylate transporters and in turn, defeating the cancer disease by arresting the cancer cells along with silencing tumour microenvironment.