Interplay between paclitaxel, gap junctions, and kinases: unraveling mechanisms of action and resistance in cancer therapy.

This comprehensive review elucidates the multifaceted roles of paclitaxel, a key chemotherapeutic agent, in cancer therapy, with a focus on its interactions with gap junctions and related kinases. Paclitaxel, with its complex diterpene structure, mediates its anticancer effects predominantly through specific interactions with ß-tubulin, instigating cell cycle arrest and triggering various cell death pathways, including apoptosis, pyroptosis, ferroptosis, and necroptosis. The paper systematically delineates the chemical attributes and action mechanisms of paclitaxel and its analogs, underscoring their capacity to disrupt microtubule dynamics, thereby leading to mitotic arrest and subsequent cell death induction. It also scrutinizes the pivotal role of gap junctions, composed of connexin proteins, in the modulation of cancer cell behavior and chemoresistance, especially in the milieu of paclitaxel administration. The review articulates how gap junctions can either suppress tumors or contribute to cancer progression, thereby influencing chemotherapy outcomes. Furthermore, the paper provides an in-depth analysis of how paclitaxel modulates gap junction-associated kinases via phosphorylation, influencing the drug's therapeutic efficacy and resistance profiles. By integrating insights from numerous key studies, the review offers a comprehensive understanding of the interplay between paclitaxel, gap junctions, and kinases, shedding light on potential approaches to augment paclitaxel's anti-tumor effectiveness and counteract chemoresistance in cancer treatment.

Exploring the Role of Surface and Mitochondrial ATP-Sensitive Potassium Channels in Cancer: From Cellular Functions to Therapeutic Potentials.

ATP-sensitive potassium (KATP) channels are found in plasma membranes and mitochondria. These channels are a type of ion channel that is regulated by the intracellular concentration of adenosine triphosphate (ATP) and other nucleotides. In cell membranes, they play a crucial role in linking metabolic activity to electrical activity, especially in tissues like the heart and pancreas. In mitochondria, KATP channels are involved in protecting cells against ischemic damage and regulating mitochondrial function. This review delves into the role of KATP channels in cancer biology, underscoring their critical function. Notably responsive to changes in cellular metabolism, KATP channels link metabolic states to electrical activity, a feature that becomes particularly significant in cancer cells. These cells, characterized by uncontrolled growth, necessitate unique metabolic and signaling pathways, differing fundamentally from normal cells. Our review explores the intricate roles of KATP channels in influencing the metabolic and ionic balance within cancerous cells, detailing their structural and operational mechanisms. We highlight the channels' impact on cancer cell survival, proliferation, and the potential of KATP channels as therapeutic targets in oncology. This includes the challenges in targeting these channels due to their widespread presence in various tissues and the need for personalized treatment strategies. By integrating molecular biology, physiology, and pharmacology perspectives, the review aims to enhance the understanding of cancer as a complex metabolic disease and to open new research and treatment avenues by focusing on KATP channels. This comprehensive approach provides valuable insights into the potential of KATP channels in developing innovative cancer treatments.

Curcumin in Cancer and Inflammation: An In-Depth Exploration of Molecular Interactions, Therapeutic Potentials, and the Role in Disease Management.

This paper delves into the diverse and significant roles of curcumin, a polyphenolic compound from the Curcuma longa plant, in the context of cancer and inflammatory diseases. Distinguished by its unique molecular structure, curcumin exhibits potent biological activities including anti-inflammatory, antioxidant, and potential anticancer effects. The research comprehensively investigates curcumin's molecular interactions with key proteins involved in cancer progression and the inflammatory response, primarily through molecular docking studies. In cancer, curcumin's effectiveness is determined by examining its interaction with pivotal proteins like CDK2, CK2α, GSK3ß, DYRK2, and EGFR, among others. These interactions suggest curcumin's potential role in impeding cancer cell proliferation and survival. Additionally, the paper highlights curcumin's impact on inflammation by examining its influence on proteins such as COX-2, CRP, PDE4, and MD-2, which are central to the inflammatory pathway. In vitro and clinical studies are extensively reviewed, shedding light on curcumin's binding mechanisms, pharmacological impacts, and therapeutic application in various cancers and inflammatory conditions. These studies are pivotal in understanding curcumin's functionality and its potential as a therapeutic agent. Conclusively, this review emphasizes the therapeutic promise of curcumin in treating a wide range of health issues, attributed to its complex chemistry and broad pharmacological properties. The research points towards curcumin's growing importance as a multi-faceted natural compound in the medical and scientific community.

A comprehensive review of the effects of resveratrol on glucose metabolism: unveiling the molecular pathways and therapeutic potential in diabetes management.

Resveratrol, a naturally occurring polyphenolic compound predominantly found in red wine and grapes, has garnered attention for its potential role in regulating carbohydrate digestion, glucose absorption, and metabolism. This review aims to deliver a comprehensive analysis of the molecular mechanisms and therapeutic potential of resveratrol in influencing vital processes in glucose homeostasis. These processes include carbohydrate digestion, glucose absorption, glycogen storage, insulin secretion, glucose metabolism in muscle cells, and triglyceride synthesis in adipocytes.The goal of this review is to offer an in-depth understanding of the multifaceted effects of resveratrol on glucose metabolism. By doing so, it presents valuable insights into its potential applications for preventing and treating metabolic disorders. This comprehensive examination of resveratrol's impact on glucose management will contribute to the growing body of knowledge on this promising natural compound, which may benefit researchers, healthcare professionals, and individuals interested in metabolic disorder prevention and treatment.

Calcium's Role in Orchestrating Cancer Apoptosis: Mitochondrial-Centric Perspective.

Calcium is an essential intracellular messenger that plays a vital role in controlling a broad range of cellular processes, including apoptosis. This review offers an in-depth analysis of calcium's multifaceted role in apoptosis regulation, focusing on the associated signaling pathways and molecular mechanisms. We will explore calcium's impact on apoptosis through its effects on different cellular compartments, such as the mitochondria and endoplasmic reticulum (ER), and discuss the connection between calcium homeostasis and ER stress. Additionally, we will highlight the interplay between calcium and various proteins, including calpains, calmodulin, and Bcl-2 family members, and the role of calcium in regulating caspase activation and pro-apoptotic factor release. By investigating the complex relationship between calcium and apoptosis, this review aims to deepen our comprehension of the fundamental processes, and pinpointing possible treatment options for illnesses associated with imbalanced cell death is crucial.

NADPH Dynamics: Linking Insulin Resistance and ß-Cells Ferroptosis in Diabetes Mellitus.

This review offers an in-depth exploration of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) in metabolic health. It delves into how NADPH affects insulin secretion, influences insulin resistance, and plays a role in ferroptosis. NADPH, a critical cofactor in cellular antioxidant systems and lipid synthesis, plays a central role in maintaining metabolic homeostasis. In adipocytes and skeletal muscle, NADPH influences the pathophysiology of insulin resistance, a hallmark of metabolic disorders such as type 2 diabetes and obesity. The review explores the mechanisms by which NADPH contributes to or mitigates insulin resistance, including its role in lipid and reactive oxygen species (ROS) metabolism. Parallelly, the paper investigates the dual nature of NADPH in the context of pancreatic ß-cell health, particularly in its relation to ferroptosis, an iron-dependent form of programmed cell death. While NADPH's antioxidative properties are crucial for preventing oxidative damage in ß-cells, its involvement in lipid metabolism can potentiate ferroptotic pathways under certain pathological conditions. This complex relationship underscores the delicate balance of NADPH homeostasis in pancreatic health and diabetes pathogenesis. By integrating findings from recent studies, this review aims to illuminate the nuanced roles of NADPH in different tissues and its potential as a therapeutic target. Understanding these dynamics offers vital insights into the development of more effective strategies for managing insulin resistance and preserving pancreatic ß-cell function, thereby advancing the treatment of metabolic diseases.

Diplacone Isolated from Paulownia tomentosa Mature Fruit Induces Ferroptosis-Mediated Cell Death through Mitochondrial Ca2+ Influx and Mitochondrial Permeability Transition.

The recently defined type of cell death ferroptosis has garnered significant attention as a potential new approach to cancer treatment owing to its more immunogenic nature when compared with apoptosis. Ferroptosis is characterized by the depletion of glutathione (GSH)/glutathione peroxidase-4 (GPx4) and iron-dependent lipid peroxidation. Diplacone (DP), a geranylated flavonoid compound found in Paulownia tomentosa fruit, has been identified to have anti-inflammatory and anti-radical activity. In this study, the potential anticancer activity of DP was explored against A549 human lung cancer cells. It was found that DP induced a form of cytotoxicity distinct from apoptosis, which was accompanied by extensive mitochondrial-derived cytoplasmic vacuoles. DP was also shown to increase mitochondrial Ca2+ influx, reactive oxygen species (ROS) production, and mitochondrial permeability transition (MPT) pore-opening. These changes led to decreases in mitochondrial membrane potential and DP-induced cell death. DP also induced lipid peroxidation and ATF3 expression, which are hallmarks of ferroptosis. The ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 were effective in counteracting the DP-mediated ferroptosis-related features. Our results could contribute to the use of DP as a ferroptosis-inducing agent, enabling studies focusing on the relationship between ferroptosis and the immunogenic cell death of cancer cells.

Tripterygium regelii decreases the biosynthesis of triacylglycerol and cholesterol in HepG2 cells.

In the course of screening to find a plant material decreasing the activity of triacylglycerol and cholesterol, we identified Tripterygium regelii (TR). The methanol extract of TR leaves (TR-LM) was shown to reduce the intracellular lipid contents consisting of triacylglycerol (TG) and cholesterol in HepG2 cells. TR-LM also downregulated the mRNA and protein expression of the lipogenic genes such as SREBP-1 and its target enzymes. Consequently, TR-LM reduced the TG biosynthesis in HepG2 cells. In addition, TR-LM decreased SREBP2 and its target enzyme HMG-CoA reductase, which is involved in cholesterol synthesis. In this study, we evaluated that TR-LM attenuated cellular lipid contents through the suppression of de novo TG and cholesterol biosynthesis in HepG2 cells. All these taken together, TR-LM could be beneficial in regulating lipid metabolism and useful preventing the hyperlipidemia and its complications, in that liver is a crucial tissue for the secretion of serum lipids.

Oleanane-type triterpenoids of Aceriphyllum rossii and their diacylglycerol acyltransferase-inhibitory activity.

Six known triterpenoid compounds, 3-oxoolean-12-en-27-oic acid (1), gypsogenic acid (2), 3α-hydroxyolean-12-en-27-oic acid (3), 3ß-hydroxyolean-12-en-27-oic acid (4), aceriphyllic acid A (5), and oleanolic acid (6), were isolated from the roots of Aceriphyllum rossii. Their chemical structures were determined by comparison with available (1)H-NMR and (13)C-NMR data on known compounds. All the isolated compounds were evaluated for inhibitory activity against human diacylglycerol acyltransferases 1 and 2. Most of the isolates exhibited a better inhibitory activity against diacylglycerol acyltransferase 2 (IC50: 11.6-44.2 µM) than against diacylglycerol acyltransferase 1 (IC50: 22.7-119.5 µM). In particular, compounds 1 and 5 showed strong inhibition efficacy towards diacylglycerol acyltransferases 1 and 2, and appeared to act competitively against oleoyl-CoA in vitro. The results also indicated that both compounds reduced newly synthesized triacylglycerol in HuTu80 and HepG2 cells. Oral administration of compound 1 significantly reduced postprandial triacylglycerol in mice following an oral lipid challenge. In conclusion, the current study indicates that compound 1 suppresses both de novo triacylglycerol biosynthesis and resynthesis through the inhibition of diacylglycerol acyltransferase activity, and therefore may be a useful agent for treating diseases associated with a high triacylglycerol level.

Deciphering the Role of BCAR3 in Cancer Progression: Gene Regulation, Signal Transduction, and Therapeutic Implications.

This review comprehensively explores the gene BCAR3, detailing its regulation at the gene, mRNA, and protein structure levels, and delineating its multifunctional roles in cellular signaling within cancer contexts. The discussion covers BCAR3's involvement in integrin signaling and its impact on cancer cell migration, its capability to induce anti-estrogen resistance, and its significant functions in cell cycle regulation. Further highlighted is BCAR3's modulation of immune responses within the tumor microenvironment, a novel area of interest that holds potential for innovative cancer therapies. Looking forward, this review outlines essential future research directions focusing on transcription factor binding studies, isoform-specific expression profiling, therapeutic targeting of BCAR3, and its role in immune cell function. Each segment builds towards a holistic understanding of BCAR3's operational mechanisms, presenting a critical evaluation of its therapeutic potential in oncology. This synthesis aims to not only extend current knowledge but also catalyze further research that could pivotally influence the development of targeted cancer treatments.

Rotundifuran Induces Ferroptotic Cell Death and Mitochondria Permeability Transition in Lung Cancer Cells.

Rotundifuran (RF), a potent anti-inflammatory and anti-cancer compound, is a natural compound predominantly present in Vitex Rotundifolia. Herein, we investigated the effects of RF on the growth of lung cancer cells. Our findings suggested that RF inhibits cell growth, highlighting its potential as a therapeutic agent for cancer treatment. Interestingly, we observed that cell growth inhibition was not due to apoptosis, as caspases were not activated and DNA fragmentation did not occur. Furthermore, we found that intracellular vacuoles and autophagy were induced, but RF-induced cell death was not affected when autophagy was inhibited. This prompted us to investigate other possible mechanisms underlying cell growth inhibition. Through a cDNA chip analysis, we confirmed changes in the expression of ferroptosis-related genes and observed lipid peroxidation. We further examined the effect of ferroptosis inhibitors and found that they alleviated cell growth inhibition induced by RF. We also observed the involvement of calcium signaling, ROS accumulation, and JNK signaling in the induction of ferroptosis. Our findings suggested that RF is a potent anti-cancer drug and further studies are needed to validate its clinal use.

Garcinia mangostana Suppresses Triacylglycerol Synthesis in Hepatocytes and Enterocytes.

Regulation of diacylglycerol acyltransferase (DGAT) and pancreatic lipase (PL) activities is important in the treatment of triacylglycerol (TG)-related metabolic diseases. Garcinia mangostana, also known as mangosteen, is a traditional medicine ingredient used in the treatment of inflammation in Southeast Asia. In this study, The ethanolic extract of G. mangostana peel inhibited human recombinant DGAT1 and DGAT2, and PL enzyme activities in vitro. The inhibitory activity of DGAT1 and DGAT2 enzymes of four representative bioactive substances in mangosteen was confirmed. In addition, G. mangostana was confirmed to suppress the serum TG levels in C57 mice by inhibiting the absorption and synthesis of TG in the gastrointestinal tract. Through this study, it was revealed that G. mangostana extract could be useful for the prevention and amelioration of TG-related metabolic diseases such as obesity and fatty liver.

Capsaicin sensitizes TRAIL-induced apoptosis through Sp1-mediated DR5 up-regulation: involvement of Ca(2+) influx.

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various malignant cells, several cancers including human hepatocellular carcinoma (HCC) exhibit potent resistance to TRAIL-induced cell death. The aim of this study is to evaluate the anti-cancer potential of capsaicin in TRAIL-induced cancer cell death. As indicated by assays that measure phosphatidylserine exposure, mitochondrial activity and activation of caspases, capsaicin potentiated TRAIL-resistant cells to lead to cell death. In addition, we found that capsaicin induces the cell surface expression of TRAIL receptor DR5, but not DR4 through the activation Sp1 on its promoter region. Furthermore, we investigated that capsaicin-induced DR5 expression and apoptosis are inhibited by calcium chelator or inhibitors for calmodulin-dependent protein kinase. Taken together, our data suggest that capsaicin sensitizes TRAIL-mediated HCC cell apoptosis by DR5 up-regulation via calcium influx-dependent Sp1 activation.

Protuboxepin A, a marine fungal metabolite, inducing metaphase arrest and chromosomal misalignment in tumor cells.

Previously we reported the identification of a new oxepin-containing diketopiperazine-type marine fungal metabolite, named protuboxepin A which showed antiproliferative activity in several cancer cell lines. In this study we elucidated the mechanism by which protuboxepin A induces cancer cell growth inhibition. Here we report that protuboxepin A induced round-up morphology, M phase arrest, and an increase in the subG(1) population in tumor cells in a dose dependent manner. Our investigations revealed that protuboxepin A directly binds to α,ß-tubulin and stabilizes tubulin polymerization thus disrupting microtubule dynamics. This disruption leads to chromosome misalignment and metaphase arrest which induces apoptosis in cancer. Overall, we identified protuboxepin A as a microtubule-stabilizing agent which has a distinctly different chemical structure from previously reported microtubule inhibitors. These results indicate that protuboxepin A has a potential of being a new and effective anti-cancer drug.

Role of p21 in SP600125-induced cell cycle arrest, endoreduplication, and apoptosis.

The anti-cancer effect of the c-Jun N-terminal kinase (JNK) inhibitor SP600125 has been well evaluated in human cancer cells. However the role of p21 in SP600125-mediated G(2)/M distribution is not fully understood. Our results showed that the transcriptional activation of p21 by SP600125 is mediated through the proximal regions of multiple Sp1 sites in the p21 promoter following ERK-dependent phosphorylation of Sp1. In this process, p21 induces endoreduplication through the inhibition of cyclin E/Cdk2 activity at 24 h but does not directly regulate cyclin B1/Cdc2 activity. Furthermore, SP600125 induces the phosphorylation of p21 at Thr 145 through the PI3K/Akt pathway. Akt-mediated phosphorylation of p21 and protection of apoptosis are completely abolished by inhibitors of PI3K and Akt. In summary using time points, we identified the dual functions of p21 as an inhibitor of cell-cycle progression at 24 h and as an anti-apoptotic factor at 48 h.

Violaceols function as actin inhibitors inducing cell shape elongation in fibroblast cells.

Violaceol-I and -II were isolated from a fractionated library of marine-derived fungal metabolites. These compounds increased the calcium ion concentration inside the cell and caused F-actin aggregation in rat fibroblast 3Y1 cells within 3 h resulting in cell shape elongation. Calcium chelator BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester) inhibited violaceol-I and -II induced F-actin aggregation in 3Y1 cells, and hence violaceol-I and -II act in a calcium dependent manner. Violaceol-I and -II inhibited G-actin polymerization in vitro in a dose-dependent manner and strongly associated with G-actin, at dissociation equilibrium constants of 1.44 × 10(-8) M and 2.52 × 10(-9) M respectively. Here we report the identification of a novel function of violaceol-I and -II as actin inhibitors. Violaceol-I and -II induced cell shape elongation through F-actin aggregation in 3Y1 fibroblasts. These compounds may give researchers new insights into the role of actin in tumorigenesis and lead to the development of additional anti-tumor drugs.

Fusarisetin A, an acinar morphogenesis inhibitor from a soil fungus, Fusarium sp. FN080326.

An acinar morphogenesis inhibitor named fusarisetin A (1) that possesses both an unprecedented carbon skeleton and a new pentacyclic ring system has been identified from an in-house fractionated fungal library using a three-dimensional matrigel-induced acinar morphogenesis assay system. The structure of 1 was determined in detail by NMR and circular dichroism spectroscopy, X-ray analysis, and chemical reaction experiments.

Agaricus blazei Extract Induces Apoptosis through ROS-Dependent JNK Activation Involving the Mitochondrial Pathway and Suppression of Constitutive NF-κB in THP-1 Cells.

Agaricus blazei is widely accepted as a traditional medicinal mushroom, and it has been known to exhibit immunostimulatory and anti-cancer activity. However, the apoptotic mechanism in cancer cells is poorly understood. In this study, we have investigated whether A. blazei extract (ABE) exerts antiproliferative and apoptotic effects in human leukemic THP-1 cells. We observed that ABE-induced apoptosis is associated with the mitochondrial pathway, which is mediated by reactive oxygen species (ROS) generation and prolonged c-Jun N-terminal kinase (JNK) activation. In addition, the ABE treatment resulted in the accumulation of cytochrome c in the cytoplasm, an increase in caspase activity, and an upregulation of Bax and Bad. With those results in mind, we found that ABE decreases constitutive NF-κB activation and NF-κB-regulated gene products such as IAP-1 and -2. We concluded that ABE induces apoptosis with ROS-dependent JNK activation and constitutive activated NF-κB inhibition in THP-1 cells.

A novel Fas ligand in mollusk abalone: molecular characterization, immune responses and biological activity of the recombinant protein.

Fas ligand is a member of the TNF superfamily that plays an important role by inducing apoptosis and homeostasis of immune responses. The gene encoding Fas ligand was isolated from a disk abalone (Haliotis discus discus) cDNA library, denoted as the AbFas ligand. It contains an 1832bp transcript with a 945bp open reading frame, encoding 315 amino acids. The AbFas ligand showed characteristic transmembrane and TNF family signature domains. The deduced amino acid comparison showed that the AbFas ligand exhibits 22.0, 16.1 and 14.5% identities to human Fas ligand, TNF-alpha, and lymphotoxin (LT-alpha), respectively. Phylogenetic analysis indicates that the AbFas ligand belongs to the invertebrate TNF family and it is closely related to vertebrate Fas ligand counterparts. Quantitative real-time PCR analysis results showed that the AbFas ligand transcripts were constitutively expressed in abalone hemocytes, gills, mantle, muscle, digestive tract and digestive gland in a tissue-specific manner. By immune stimulation, AbFas ligand mRNA was significantly (p<0.05) up-regulated after infection with a mixture of bacteria (Vibrio alginolyticus, Vibrio parahemolyticus, and Listeria monocytogenes), viral haemorrhagic septicaemia virus (VHSV), and lipopolysaccharide (LPS) in abalone gills. The recombinant AbFas ligand was over-expressed in Escherichia coli (E. coli) and purified using a pMAL protein fusion system. This recombinant AbFas ligand showed its biological activity by inducing both superoxide anion (O(2-) and H(2)O(2) in human THP-1 cells in concentration-dependant manner. Correlating the AbFas ligand transcriptional up-regulation against bacteria, virus and LPS with the biological activity of its recombinant protein, we could suggest that the abalone Fas ligand may control microbial infection by inducing O(2-), H(2)O(2) and other ROS.

Gefitinib induces apoptosis and decreases telomerase activity in MDA-MB-231 human breast cancer cells.

Gefitinib is an anti-cancer drug that selectively inhibits epithelial growth factor receptor (EGFR) tyrosine kinase activity and induces apoptosis in many cancer cells. Cancer cells are often protected from apoptotic cell death by telomerase, however the gefitinib-induced telomerase inhibition remains unknown. Here we investigated the effects of gefitinib on telomerase activity in two different breast cancer lines, MCF-7 (low expression of EGFR) and MDA-MB-231 (high expression of EGFR). We observed the inhibition of EGFR phosphorylation that occurred only MDA-MB-231 cells cultured in media containing 10% FBS. Direct cytotoxicity was observed in MDA-MB-231 cells, but not MCF-7 cells when treated with concentrations of gefitinib ranging from 15 to 20 microM. This cytotoxicity was associated with decreased telomerase activity and downregulation of the telomerase subunit, hTERT. c-Myc has previously been shown to activate telomerase activity through transcriptional regulation of hTERT. A decrease in c-myc expression and DNA-binding activity following treatment with gefitinib was observed exclusively in MDA-MB-231 cells. We also demonstrated that gefitinib downregulates the activation of Akt and subsequent hTERT phosphorylation and translocation into the nucleus in MDA-MB-231 cells. These results indicate that gefitinib induces loss of telomerase activity through dephosphorylation of EGFR in MDA-MB-231 cells.