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In this paper, we present the synthesis and characterization of two known sulfonyl hydrazides (1 and 2) and their new sulfonyl hydrazone derivatives (9–20), as well as in vitro and in silico investigations of their cytotoxic properties against human lung (A549) and human breast (MCF-7) cancer cell lines. The target compounds (9–20) obtained in high yields were synthesized for the first time by a multi-step reaction, and their structures were confirmed by elemental analysis and various spectral techniques, including FT-IR, 1H-, and 13C-NMR. The antiproliferative profiles of these compounds (1, 2, and 9–20) in this study were determined at concentrations of 200, 100, 50, and 25 µM against selected cancer cell lines for 72 h using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. Except for compounds 1 and 2, other compounds (9–20) demonstrated cytotoxic activity at concentrations lower than 200 µM. The newly synthesized compounds (9–20) demonstrated antiproliferative activities at a micromolar level, with IC50 values in the range of 29.59–176.70 μM for the A549 cell line and 27.70–170.30 μM for the MCF-7 cell line. Among these compounds, compound 15 (IC50 = 29.59 μM against A549 cell line and IC50 = 27.70 μM against MCF-7 cell line) showed the highest cytotoxic activity against these two cancer cell lines compared to the reference drug cisplatin (IC50 = 22.42 μM against A549 cell line and IC50 = 18.01 μM against MCF-7 cell line). From docking simulations, to establish a plausible binding mode of compounds, we noticed that compound 15 demonstrated the highest affinity (−6.8508 kcal/mol) for estrogen receptor-beta (ERbeta) compared to others, suggesting promising ERbeta binding potential. Most compounds followed Lipinski's rule of five, with acceptable logP values. Additionally, all had mixed gastrointestinal absorption and limited blood–brain barrier permeability. Overall, our study proposed new sulfonyl hydrazones as a potential class of anticancer agents. [ABSTRACT FROM AUTHOR]

Abstract Background Multidrug resistance (MDR) limits successful cancer chemotherapy. P-glycoprotein (P-gp), BCRP and MRP1 are the key triggers of MDR. Unfortunately, no MDR modulator was approved by FDA to date. Here, we will investigate the effect of BI-2865, a pan-KRAS inhibitor, on reversing MDR induced by P-gp, BCRP and MRP1 in vitro and in vivo, and its reversal mechanisms will be explored. Methods The cytotoxicity of BI-2865 and its MDR removal effect in vitro were tested by MTT assays, and the corresponding reversal function in vivo was assessed through the P-gp mediated KBv200 xenografts in mice. BI-2865 induced alterations of drug discharge and reservation in cells were estimated by experiments of Flow cytometry with fluorescent doxorubicin, and the chemo-drug accumulation in xenografts’ tumor were analyzed through LC-MS. Mechanisms of BI-2865 inhibiting P-gp substrate’s efflux were analyzed through the vanadate-sensitive ATPase assay, [125I]-IAAP-photolabeling assay and computer molecular docking. The effects of BI-2865 on P-gp expression and KRAS-downstream signaling were detected via Western blotting, Flow cytometry and/or qRT-PCR. Subcellular localization of P-gp was visualized by Immunofluorescence. Results We found BI-2865 notably fortified response of P-gp-driven MDR cancer cells to the administration of chemo-drugs including paclitaxel, vincristine and doxorubicin, while such an effect was not observed in their parental sensitive cells and BCRP or MRP1-driven MDR cells. Importantly, the mice vivo combination study has verified that BI-2865 effectively improved the anti-tumor action of paclitaxel without toxic injury. In mechanism, BI-2865 prompted doxorubicin accumulating in carcinoma cells by directly blocking the efflux function of P-gp, which more specifically, was achieved by BI-2865 competitively binding to the drug-binding sites of P-gp. What’s more, at the effective MDR reversal concentrations, BI-2865 neither varied the expression and location of P-gp nor reduced its downstream AKT or ERK1/2 signaling activity. Conclusions This study uncovered a new application of BI-2865 as a MDR modulator, which might be used to effectively, safely and specifically improve chemotherapeutic efficacy in the clinical P-gp mediated MDR refractory cancers.

Background: Multidrug resistance (MDR) limits successful cancer chemotherapy. P-glycoprotein (P-gp), BCRP and MRP1 are the key triggers of MDR. Unfortunately, no MDR modulator was approved by FDA to date. Here, we will investigate the effect of BI-2865, a pan-KRAS inhibitor, on reversing MDR induced by P-gp, BCRP and MRP1 in vitro and in vivo, and its reversal mechanisms will be explored. Methods: The cytotoxicity of BI-2865 and its MDR removal effect in vitro were tested by MTT assays, and the corresponding reversal function in vivo was assessed through the P-gp mediated KBv200 xenografts in mice. BI-2865 induced alterations of drug discharge and reservation in cells were estimated by experiments of Flow cytometry with fluorescent doxorubicin, and the chemo-drug accumulation in xenografts' tumor were analyzed through LC-MS. Mechanisms of BI-2865 inhibiting P-gp substrate's efflux were analyzed through the vanadate-sensitive ATPase assay, [125I]-IAAP-photolabeling assay and computer molecular docking. The effects of BI-2865 on P-gp expression and KRAS-downstream signaling were detected via Western blotting, Flow cytometry and/or qRT-PCR. Subcellular localization of P-gp was visualized by Immunofluorescence. Results: We found BI-2865 notably fortified response of P-gp-driven MDR cancer cells to the administration of chemo-drugs including paclitaxel, vincristine and doxorubicin, while such an effect was not observed in their parental sensitive cells and BCRP or MRP1-driven MDR cells. Importantly, the mice vivo combination study has verified that BI-2865 effectively improved the anti-tumor action of paclitaxel without toxic injury. In mechanism, BI-2865 prompted doxorubicin accumulating in carcinoma cells by directly blocking the efflux function of P-gp, which more specifically, was achieved by BI-2865 competitively binding to the drug-binding sites of P-gp. What's more, at the effective MDR reversal concentrations, BI-2865 neither varied the expression and location of P-gp nor reduced its downstream AKT or ERK1/2 signaling activity. Conclusions: This study uncovered a new application of BI-2865 as a MDR modulator, which might be used to effectively, safely and specifically improve chemotherapeutic efficacy in the clinical P-gp mediated MDR refractory cancers. [ABSTRACT FROM AUTHOR]

Nicotine activates nicotinic acetylcholine receptors (nAChRs), which are overexpressed in numerous cancer types, leading to signaling pathways that increase lung cancer invasiveness and resistance to chemotherapeutic agents. In this study, the effects of APS12-2, a synthetic analog of marine sponge toxin that acts as an antagonist of nAChRs, was investigated in vitro on A549 human lung adenocarcinoma cells and non-tumorigenic human lung epithelial BEAS-2B cells. In addition, gelatin nanoparticles (GNPs) loaded with APS12-2 (APS12-2-GNPs) were prepared and their effects were compared with those of free APS12-2. Nicotine reduced cytotoxicity, the formation of reactive oxygen species, and the formation of lipid droplets caused by cisplatin on A549 cells. The effects of nicotine on the decreased efficacy of cisplatin were reduced by APS12-2 and APS12-2-GNPs. APS12-2-GNPs showed a substantial advantage compared with free APS12-2; the cytotoxicity of APS12-2 on BEAS-2B cells was greatly reduced when APS12-2 was loaded in GNPs, whereas the cytotoxicity on A549 cells was only slightly reduced. Our results suggest that both APS12-2 and APS12-2-GNPs hold promise as supportive agents in the cisplatin-based chemotherapy of lung cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Phytochemicals have become a growing source of alternative medicine in developing countries due to the poor prognosis, high cost of conventional pharmaceuticals, and undesirable effects associated with mainstream cancer treatment. Objective This study was aimed at investigating the anticancer effect of some selected Nigerian medicinal plants used in cancer treatment. These include ethanol extracts of Dialium guineense root (DGR), Dialium guineense leaves (DGL), Jateorhiza macrantha leaves (JML), Musanga cecropioides leaves (MCL), Musanga cecropioides stembark (MCSB), Piptadeniastrum africanum stembark (PASB), Piptadeniastrum africanum root (PAR), Pupalia lappacea flower tops (PLF), Raphiostylis beninensis root (RBR), Raphiostylis beninensis leaves (RBL), Ritchiea capparoides leaves (RCL), Ritchiea capparoides stembark (RCSB), and Triplochiton scleroxylon stembark (TSB). Methods The cytotoxic activity of the extracts was examined using a brine shrimp lethality assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against three cancer cell lines, including MCF-7, HUH-7, and HeLa. The selectivity of all extracts towards cancer cells was investigated using normal lung fibroblasts (MRC-5). Cell migration and colony-forming assays of active extracts against MCF-7 cells were also performed. Additionally, the total polyphenolic contents of the active extracts were estimated using standard methods. Results The extract of PASB had the highest cytotoxicity (LC50 = 1.58 μg/mL) on the brine shrimps compared to vincristine sulphate (LC50 = 2.24 μg/mL). In the cell viability assay, all the extracts produced significant (p

Background Phytochemicals have become a growing source of alternative medicine in developing countries due to the poor prognosis, high cost of conventional pharmaceuticals, and undesirable efects associated with main‑ stream cancer treatment. Objective This study was aimed at investigating the anticancer efect of some selected Nigerian medicinal plants used in cancer treatment. These include ethanol extracts of Dialium guineense root (DGR), Dialium guineense leaves (DGL), Jateorhiza macrantha leaves (JML), Musanga cecropioides leaves (MCL), Musanga cecropioides stembark (MCSB), Piptadeniastrum africanum stembark (PASB), Piptadeniastrum africanum root (PAR), Pupalia lappacea fower tops (PLF), Raphiostylis beninensis root (RBR), Raphiostylis beninensis leaves (RBL), Ritchiea capparoides leaves (RCL), Ritchiea capparoides stembark (RCSB), and Triplochiton scleroxylon stembark (TSB). Methods The cytotoxic activity of the extracts was examined using a brine shrimp lethality assay and 3-(4,5-dimeth‑ ylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against three cancer cell lines, including MCF-7, HUH-7, and HeLa. The selectivity of all extracts towards cancer cells was investigated using normal lung fbroblasts (MRC-5). Cell migration and colony-forming assays of active extracts against MCF-7 cells were also performed. Additionally, the total polyphenolic contents of the active extracts were estimated using standard methods. Results The extract of PASB had the highest cytotoxicity (LC50=1.58μg/mL) on the brine shrimps compared to vin‑ cristine sulphate (LC50=2.24μg/mL). In the cell viability assay, all the extracts produced signifcant (p<0.05) growth inhibitory efects against all cell lines tested in a dose-dependent manner. All extracts were selective to cancer cells at varying degrees. Worth mentioning are the extracts of MCL, DGR, RBR, and PASB, which exhibited 14-, 7-, 6and 2-fold selectivity toward MCF-7 cancer cells relative to normal lung fbroblast (MRC-5), respectively. These four extracts also signifcantly inhibited cell migration and colony formation in MCF-7-treated cells in dose-dependent manners. Considerable amounts of phenolics, favonoids, and proanthocyanidins were detected in all extracts evaluated. Conclusion These fndings advocate the continued development of MCL, DGR, RBR, and PASB as potential chemo‑ therapeutic agents. [ABSTRACT FROM AUTHOR]

In this study, the composition of the phenolic compounds for Malva neglecta, Nerium oleander, Quercus brantii and Vitis vinifera, that are registered as traditional folk remedy used for cancer during the ethnobotanical surveys conducted in Türkiye, were analyzed in phytochemical terms. Such analysis revealed very significant (p < 0.01) content of the phenolic compounds in the chemical composition of the plants, and then the effect sizes (χ2) thereof were determined. Thus, the anticancer effect potentials of the plants were established in line with the chemotherapeutic activities of the phenolic compounds, the probable efficacy of which has been demonstrated in the content of the plants, as confirmed by the literature review. The plants, that presented the highest anti-carcinogenic activity potential on 12 established types of cancer, were: Q. brantii in bladder cancer; M. neglecta, N. oleander, Q. brantii and V. vinifera in breast cancer; Q. brantii, and V. vinifera in cervical cancer; Q. brantii and V. vinifera in colorectal cancer; N. oleander in chronic myeloid leukemia; Q. brantii in glioblastoma multiforme; M. neglecta and V. vinifera in liver cancer; M. neglecta, Q. brantii, and V. vinifera in lung cancer; Q. brantii in mesothelioma; V. vinifera in ovarian cancer; M. neglecta, and Q. brantii in prostate cancer; M. neglecta in skin cancer. [ABSTRACT FROM AUTHOR]

In this paper, we present the synthesis and characterization of two known sulfonyl hydrazides (1 and 2) and their new sulfonyl hydrazone derivatives (9–20), as well as in vitro and in silico investigations of their cytotoxic properties against human lung (A549) and human breast (MCF-7) cancer cell lines. The target compounds (9–20) obtained in high yields were synthesized for the first time by a multi-step reaction, and their structures were confirmed by elemental analysis and various spectral techniques, including FT-IR, 1H-, and 13C-NMR. The antiproliferative profiles of these compounds (1, 2, and 9–20) in this study were determined at concentrations of 200, 100, 50, and 25 µM against selected cancer cell lines for 72 h using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. Except for compounds 1 and 2, other compounds (9–20) demonstrated cytotoxic activity at concentrations lower than 200 µM. The newly synthesized compounds (9–20) demonstrated antiproliferative activities at a micromolar level, with IC50 values in the range of 29.59–176.70 μM for the A549 cell line and 27.70–170.30 μM for the MCF-7 cell line. Among these compounds, compound 15 (IC50 = 29.59 μM against A549 cell line and IC50 = 27.70 μM against MCF-7 cell line) showed the highest cytotoxic activity against these two cancer cell lines compared to the reference drug cisplatin (IC50 = 22.42 μM against A549 cell line and IC50 = 18.01 μM against MCF-7 cell line). From docking simulations, to establish a plausible binding mode of compounds, we noticed that compound 15 demonstrated the highest affinity (−6.8508 kcal/mol) for estrogen receptor-beta (ERbeta) compared to others, suggesting promising ERbeta binding potential. Most compounds followed Lipinski’s rule of five, with acceptable logP values. Additionally, all had mixed gastrointestinal absorption and limited blood–brain barrier permeability. Overall, our study proposed new sulfonyl hydrazones as a potential class of anticancer agents.

Nicotine activates nicotinic acetylcholine receptors (nAChRs), which are overexpressed in numerous cancer types, leading to signaling pathways that increase lung cancer invasiveness and resistance to chemotherapeutic agents. In this study, the effects of APS12-2, a synthetic analog of marine sponge toxin that acts as an antagonist of nAChRs, was investigated in vitro on A549 human lung adenocarcinoma cells and non-tumorigenic human lung epithelial BEAS-2B cells. In addition, gelatin nanoparticles (GNPs) loaded with APS12-2 (APS12-2-GNPs) were prepared and their effects were compared with those of free APS12-2. Nicotine reduced cytotoxicity, the formation of reactive oxygen species, and the formation of lipid droplets caused by cisplatin on A549 cells. The effects of nicotine on the decreased efficacy of cisplatin were reduced by APS12-2 and APS12-2-GNPs. APS12-2-GNPs showed a substantial advantage compared with free APS12-2; the cytotoxicity of APS12-2 on BEAS-2B cells was greatly reduced when APS12-2 was loaded in GNPs, whereas the cytotoxicity on A549 cells was only slightly reduced. Our results suggest that both APS12-2 and APS12-2-GNPs hold promise as supportive agents in the cisplatin-based chemotherapy of lung cancer.

Gliomas are the second most common primary brain tumor in dogs and although they are associated with a poor prognosis, limited data are available relating to the efficacy of standard therapeutic options such as surgery, radiation and chemotherapy. Additionally, canine glioma is gaining relevance as a naturally occurring animal model that recapitulates human disease with fidelity. There is an intense comparative research drive to test new therapeutic approaches in dogs and assess if results translate efficiently into human clinical trials to improve the poor outcomes associated with the current standard-of-care. However, the paucity of data and controversy around most appropriate treatment for intracranial gliomas in dogs make comparisons among modalities troublesome. To further inform therapeutic decision-making, client discussion, and future studies evaluating treatment responses, the outcomes of 127 dogs with intracranial glioma, either presumed (n = 49) or histologically confirmed (n = 78), that received chemotherapy as leading or adjuvant treatment are reviewed here. This review highlights the status of current chemotherapeutic approaches to intracranial gliomas in dogs, most notably temozolomide and lomustine; areas of novel treatment currently in development, and difficulties to consensuate and compare different study observations. Finally, suggestions are made to facilitate evidence-based research in the field of canine glioma therapeutics.

Ovarian cancer has been one of the serious concerns for female health and medicinal practitioner all over the world. The wellness of over cancer patient is associated with survival responses which depends on many factors including chemotherapeutic diversity; treatment protocol; dose-dependent toxicity such as hematological toxicity and non-hematological toxicity. We found that the studied treatment regimens (TRs) (1–9) showed varying degree of hematological toxicities like moderate neutropenia (< 20%) critical neutropenia (> 20%), negligible leucopenia, critical leucopenia (> 20%), moderate thrombocytopenia (< 20%), critical thrombocytopenia (> 20%), moderate anemia (< 20%) and critical anemia (> 20%). The studied TRs showed varying degree of non-hematological toxicities like moderate nausea-vomiting (< 20%), critical nausea-vomiting (> 20%), moderate alopecia (< 20%), critical alopecia (> 20%), moderate fatigue (< 20%), critical fatigue (> 20%), moderate neurotoxicity (< 20%), critical neurotoxicity (> 20%), moderate diarrheas (< 20%). The studied TRs showed varying degree of survival responses like critical partial response (> 35%), remarkable overall responses (> 60%), critical overall responses (< 60%), remarkable stable disease (> 20%), critical stable disease (< 20%) and moderate progressive disease (< 20%). Out of the studied TRs 1–9, in case of TR 6, moderate non-hematological toxicity (NHT) and effective survival response (SR) is being diluted by critical hematological toxicity (HT). On the other hand, TR 8, 9 is showing critical HT, NHT and SR. Our analysis revealed that the toxicity of the existing therapeutic agents can be controlled through judicious decision of drug administration cycles and combination therapies. [ABSTRACT FROM AUTHOR]

Background & aimsGrowth, progression, and drug resistance of pancreatic ductal adenocarcinomas (PDACs) have been associated with increased levels and activity of glycogen synthase kinase 3 beta (GSK3B) and histone deacetylases (HDACs). We designed and synthesized molecules that simultaneously inhibit the activities of both enzymes. We tested the effects of one of these molecules, Metavert, in pancreatic cancer cells and mice with pancreatic tumors.MethodsWe tested the ability of Metavert to bind GSK3B and HDACs using surface plasmon resonance. MIA PaCa-2, Bx-PC3, HPAF-II, and HPDE6 cell lines were incubated with different concentrations of Metavert, with or without paclitaxel or gemcitabine, or with other inhibitors of GSK3B and HDACs; cells were analyzed for apoptosis and migration and by immunoblotting, immunofluorescence, and real-time polymerase chain reaction. Krasþ/LSLG12D;Trp53þ/LSLR172H;Pdx-1-Cre (KPC) mice (2 months old) were given injections of Metavert (5 mg/kg, 3 times/week) or vehicle (control). B6.129J mice with tumors grown from UN-KPC961-Luc cells were given injections of Metavert or vehicle. Tumors and metastases were counted and pancreata were analyzed by immunohistochemistry. Glucose metabolism was measured using 13C-glucose tracer and mass spectroscopy and flow cytometry. Cytokine levels in blood samples were measured using multiplexing enzyme-linked immunosorbent assay.ResultsMetavert significantly reduced survival of PDAC cells but not nontransformed cells; the agent reduced markers of the epithelial-to-mesenchymal transition and stem cells in PDAC cell lines. Cells incubated with Metavert in combination with irradiation and paclitaxel or gemcitabine had reduced survival compared with cells incubated with either agent alone; Metavert increased killing of drug-resistant PDAC cells by paclitaxel and gemcitabine. PDAC cells incubated with Metavert acquired normalized glucose metabolism. Administration of Metavert (alone or in combination with gemcitibine) to KPC mice or mice with syngeneic tumors significantly increased their survival times, slowed tumor growth, prevented tumor metastasis, decreased tumor infiltration by tumor-associated macrophages, and decreased blood levels of cytokines.ConclusionsIn studies of PDAC cells and 2 mouse models of PDAC, we found a dual inhibitor of GSK3B and HDACs (Metavert) to induce cancer cell apoptosis, reduce migration and expression of stem cell markers, and slow growth of tumors and metastases. Metavert had synergistic effects with gemcitabine.

The use of chemotherapeutic agents can cause side effects that have a negative impact on the patient's quality of life and have the potential to cause unexpected reactions. This reaction is known as a hypersensitivity reaction where. This reaction occurs at therapeutic doses that resemble an allergic reaction. The effects of these reactions can range from mild to life-threatening. The use of diphenhydramine as a chemotherapy premedication has been widely studied for its effectiveness in reducing the risk of hypersensitivity and toxicity from the use of chemotherapeutic agents. Therefore, this review article aims to provide an understanding of the importance of the use of premedication, as prevention of hypersensitivity reactions and reduce the potential for toxicity from the use of chemotherapeutic agents. The method used in this literature study is to identify and review various research articles through the MeSH PubMed database, ScienceDirect with the keywords "Diphenhydramine", "Prevention", "Premedication", "Hypersensitivity Reaction" "Toxicity" and "Chemotherapy" as relevant references. An analysis was conducted on relevant research articles related to the mechanism and efficacy of diphenhydramine in the use of chemotherapy. The research article that forms the basis for writing this literature study, as a whole, shows that the use of diphenhydramine as an anti-histamine is one of the effective prophylaxis that can be used before the use of chemotherapy agents to minimize the occurrence of unwanted hypersensitivity and toxicity effects. [ABSTRACT FROM AUTHOR]

Breast cancer continues to be a major global health challenge, driving the need for effective therapeutic strategies. Cisplatin, a powerful chemotherapeutic agent, is widely used in breast cancer treatment. However, its effectiveness is often limited by systemic toxicity and the development of drug resistance. This review examines the molecular factors that influence cisplatin response and resistance, offering crucial insights for the scientific community. It highlights the significance of understanding cisplatin resistance's genetic and epigenetic contributors, which could lead to more personalized treatment approaches. Additionally, the review explores innovative strategies to counteract cisplatin resistance, including combination therapies, nanoparticle-based drug delivery systems, and targeted therapies. These approaches are under intensive investigation and promise to enhance breast cancer treatment outcomes. This comprehensive discussion is a valuable resource to advance breast cancer therapeutics and address the challenge of cisplatin resistance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: 5‐Fluorouracil (5‐FU) cream is a common human topical chemotherapy agent with potentially fatal neurotoxic effects on dogs if accidentally ingested. There are seldom reports in veterinary literature describing the successful outcome of intervention after accidental ingestion of 5‐FU cream. Case Summary: A 9‐month‐old spayed female labradoodle presented 14 h after ingesting an unknown amount of 40 g tube of Efudex cream (5% 5‐FU). The dog presented in status epilepticus, which was managed with benzodiazepines and levetiracetam in conjunction with induced coma and mechanical ventilation. No further seizure activity occurred throughout the ensuing 5 days of hospitalisation; however, myelosuppression was featured. The dog was discharged home after 5 days of hospitalisation. Three days post discharge, the dog was noted to develop focal alopecia around the eyes and temporal region. 14 days after discharge, the alopecia progressed to a majority of the head and body. Conclusion: To the authors' knowledge, this is the first report that documents the enduring adverse effects of 5‐FU cream after survival of the initial episode, including an earlier onset of myelosuppression and diffuse alopecia. Successful treatment of accidental 5‐FU ingestion is possible several hours after the initial event with minimal long‐term consequences. [ABSTRACT FROM AUTHOR]

Chemotherapeutic agents, such as 5-fluorouracil (5-FU) and oxaliplatin (Oxi), can not only kill the cancer cell but also influence the proliferation of gut microbiota; however, the interaction between these drugs and gut microbiota remains poorly understood. In this study, we developed a powerful framework for taxonomy composition and genomic variation analysis to investigate the mutagenesis effect and proliferation influence of chemotherapeutic agents, such as 5-FU and Oxi, on gut microbiota and the interaction between these drugs and gut microbiota during chemotherapy. Using the gut microbiome data, we detected 1.45 million variations among the chemotherapy groups and found the drugs significantly affected mutation signatures of gut microbiota. Oxi notably increased transversion rate, whereas 5-FU reduced the rate. Traits related to cell division and nutrient mobilization showed evidence of strong selection pressure from chemotherapeutic agents. In addition, drug-associated bacteriome shift patterns and functional alterations were found: the metabolism changes in the 5-FU group implied that gut microbiota could provide additional nicotinamide adenine dinucleotide (NAD+) to inhibit cancer cell autophagy; in the Oxi group, the ribosome and lysine biosynthesis genes were obviously enriched. Our study provides a blueprint for characterizing the role of microbes and drug–microbe interaction in the gut microbiota response to chemotherapy. [ABSTRACT FROM AUTHOR]

Isatin (1H indole 2, 3-dione) is a heterocyclic, endogenous lead molecule recognized in humans and different plants. The isatin nucleus and its derivatives are owed the attention of researchers due to their diverse pharmacological activities such as anticancer, anti-TB, antifungal, antimicrobial, antioxidant, anti-inflammatory, anticonvulsant, anti-HIV, and so on. Many research chemists take advantage of the gentle structure of isatins, such as NH at position 1 and carbonyl functions at positions 2 and 3, for designing biologically active analogues via different approaches. Literature surveys based on reported preclinical, clinical, and patented details confirm the multitarget profile of isatin analogues and thus their importance in the field of medicinal chemistry as a potent chemotherapeutic agent. This review represents the recent development of isatin analogues possessing potential pharmacological action in the years 2016–2020. The structure–activity relationship is also discussed to provide a pharmacophoric pattern that may contribute in the future to the design and synthesis of potent and less toxic therapeutics. [ABSTRACT FROM AUTHOR]

Context Severe nephrotoxicity greatly limits the clinical use of the common effective chemotherapeutic agent cyclophosphamide (CYP). Huaiqihuang (HQH) is a Chinese herbal complex with various pharmacological activities, widely used for treating kidney disease. Objective This study estimates the protective effect of HQH against CYP-induced nephrotoxicity in rats. Materials and methods Four groups of 10 Sprague-Dawley rats were pre-treated with once-daily oral gavage of 3 and 6 mg/kg HQH for 5 days before receiving a single dose of CYP (200 mg/kg i.p.) on the 5th day; the control group received equivalent dose of saline. Renal function indices, morphological changes, oxidative stress, apoptosis and inflammatory mediators were measured. In addition, phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were analysed. Results Both doses of HQH reduced the levels of serum creatinine (31.27%, 43.61%), urea nitrogen (22.66%, 32.27%) and urine protein (12.87%, 15.98%) in the CYP-treated rats, and improved histopathological aberrations. Additionally, HQH decreased the production of MDA (37.02%, 46.18%) and increased the activities of antioxidant enzyme CAT (59.18%, 112.25%) and SOD (67.10%, 308.34%) after CYP treatment. HQH protected against CYP-induced nephrotoxicity by modulating apoptosis-related protein and suppressing the inflammatory responses. Furthermore, the phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were significantly boosted in CYP-treated rats, which was also abrogated by HQH treatment. Conclusions HQH effectively protected against CYP-induced nephrotoxicity, which was associated with regulating oxidative stress, apoptosis and inflammation, and so HQH may be a useful agent for treating nephrotoxicity caused by CYP.

Chemotherapeutic agents, such as 5-fluorouracil (5-FU) and oxaliplatin (Oxi), can not only kill the cancer cell but also influence the proliferation of gut microbiota; however, the interaction between these drugs and gut microbiota remains poorly understood. In this study, we developed a powerful framework for taxonomy composition and genomic variation analysis to investigate the mutagenesis effect and proliferation influence of chemotherapeutic agents, such as 5-FU and Oxi, on gut microbiota and the interaction between these drugs and gut microbiota during chemotherapy. Using the gut microbiome data, we detected 1.45 million variations among the chemotherapy groups and found the drugs significantly affected mutation signatures of gut microbiota. Oxi notably increased transversion rate, whereas 5-FU reduced the rate. Traits related to cell division and nutrient mobilization showed evidence of strong selection pressure from chemotherapeutic agents. In addition, drug-associated bacteriome shift patterns and functional alterations were found: the metabolism changes in the 5-FU group implied that gut microbiota could provide additional nicotinamide adenine dinucleotide (NAD+) to inhibit cancer cell autophagy; in the Oxi group, the ribosome and lysine biosynthesis genes were obviously enriched. Our study provides a blueprint for characterizing the role of microbes and drug–microbe interaction in the gut microbiota response to chemotherapy.

Severe nephrotoxicity greatly limits the clinical use of the common effective chemotherapeutic agent cyclophosphamide (CYP). Huaiqihuang (HQH) is a Chinese herbal complex with various pharmacological activities, widely used for treating kidney disease. This study estimates the protective effect of HQH against CYP-induced nephrotoxicity in rats. Four groups of 10 Sprague-Dawley rats were pre-treated with once-daily oral gavage of 3 and 6 mg/kg HQH for 5 days before receiving a single dose of CYP (200 mg/kg i.p.) on the 5th day; the control group received equivalent dose of saline. Renal function indices, morphological changes, oxidative stress, apoptosis and inflammatory mediators were measured. In addition, phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were analysed. Both doses of HQH reduced the levels of serum creatinine (31.27%, 43.61%), urea nitrogen (22.66%, 32.27%) and urine protein (12.87%, 15.98%) in the CYP-treated rats, and improved histopathological aberrations. Additionally, HQH decreased the production of MDA (37.02%, 46.18%) and increased the activities of antioxidant enzyme CAT (59.18%, 112.25%) and SOD (67.10%, 308.34%) after CYP treatment. HQH protected against CYP-induced nephrotoxicity by modulating apoptosis-related protein and suppressing the inflammatory responses. Furthermore, the phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were significantly boosted in CYP-treated rats, which was also abrogated by HQH treatment. HQH effectively protected against CYP-induced nephrotoxicity, which was associated with regulating oxidative stress, apoptosis and inflammation, and so HQH may be a useful agent for treating nephrotoxicity caused by CYP. [ABSTRACT FROM AUTHOR]

Objective: The objective of this article was to offer practical operational process for pharmacists to successfully conduct integrated pharmaceutical care for patients with hand-foot syndrome associated with chemotherapeutic agents and targeted drugs which may facilitate the work of first-line clinical pharmacist. Data sources: A literature review was conducted in March 2020 of Pubmed, Medline, and EMBASE (2010-2020) using terms such as: hand-foot syndrome, hand-foot skin reaction, palmar-plantar erythrodysesthesia, chemotherapeutic agent, and multikinase inhibitor. Appropriate references from selected articles were also used. Data summary: This paper involves 81 articles including review articles, meta-analysis, and clinical trials which focused on every aspect of hand-foot syndrome, such as manifestation, mechanism, occurrence rate, onset time, patient education, self-monitor scale, and management. Studies were thematically divided into four parts (clinical presentation of HFS, risk stratification, initiation of pharmaceutic care, and management of the adverse reaction). Conclusion: HFS is one of the common adverse events which was associated with many chemotherapeutic agents and multikinase inhibitor drugs. Although the mechanisms and histopathology may be different, they due share some common clinical manifestations. As part of integrated pharmaceutical care for cancer patients, it is important to conduct patient education about the risk of hand-foot syndrome and basic knowledge about hand-foot syndrome management before initiating anticancer therapy. Once hand-foot syndrome happens, evidence-based management could try. If the hand-foot syndrome is intolerable, dose reduction or discontinuation of the anticancer therapy should be considered. [ABSTRACT FROM AUTHOR]

Introduction: GLOBOCAN 2018 data indicates the incidence and mortality of colorectal cancer that is the third lethal and fourth most diagnosed cancer in the world. There has been significant progress in cancer therapy while the ability of cancerous cells to survive is one of the main challenges in cancer research. Still, conventional therapies like surgery, chemo, and radiotherapy are widely used options. Therefore, efforts put in action by researchers in the field of drug design, molecular genetics, and biomedicine to come across safer substances with the minimum unwanted side effects to be utilized in cancer treatment. Plant-derived compounds are ideal options as they might have a better outcome with minimal side effects. Methods: In the current research, the anti-cancer effect of Syzygium cumini ethanolic extract (SCE) was evaluated on the HT-29 colorectal cancer cell line. To this end, the apoptosis rate and proliferation of HT-29 cell lines after exposure to SCE were investigated through MTT, and other methods including DNA damage assessment and scratch test also employed to evaluate the metastasis and cell migration capacity of HT-29 after treatment with SCE. Behind that, expression ration of genes involved in the process of apoptosis has been studied, including Bax and Bcl-2 that were measured by qRT-PCR. Results: Based on the MTT test, SCE suppresses the growth of HT-29 cell lines drastically. Expression analysis of the ratio of desired genes (Bax: Bcl-2) also changed significantly after treatment by SCE. DNA damage test confirmed DNA lost its integrity and gone through apoptosis, and wound healing suggests the lower change of metastasis after treatment by SCE. Conclusion: The outcome of this study suggests that Syzygium cumini might be contemplating as a future chemotherapeutic agent and suitable candidate for in vivo trial. [ABSTRACT FROM AUTHOR]

Introduction: Cancer is the uncontrolled division of cells and can be caused by genetic or environmental factors. Pancreatic cancer is one of the deadliest among all cancers. The role of bacteria as an anticancer agent dates back to almost 100 years ago. The microbiome has recently become a focus of research in carcinogenesis and even pancreatic cancer. Shigella flexneri is a gram-negative bacterium, which causes shigellosis with symptoms such as diarrhea, fever, and stomach cramps in human. Shigella flexneri may play a very important role in the internal pathways of apoptosis and may induce apoptosis in some of the cancerous cells. Material and Methods: In this experiment bacteria were cultured on Salmonella-Shigella agar, then inoculated into BHI Broth medium. After sonication, the protein concentration of the bacterium was measured by using the ZellBio Sensitive Protein Bradford Assay kit. MTT assay was performed to obtain IC50 for the said bacterial protein. Later by cDNA kit synthesized the cDNA based on the RNA template. In the end, the results were analyzed using real-time PCR and the expression of Bax and Bcl-2 genes was measured before and after treatment. Results: The results showed that Shigella flexneri has the potential anti-proliferative effect in pancreatic cancer. The inhibitory concentration, pro-apoptotic amount to upregulate Bax, and meanwhile also to downregulate the bcl-2 found to be 10 μl. Conclusion: In general, due to defects in the apoptotic pathway in cancer cells and the existence of drug-resistant cells, the detection of new apoptotic inducers such as Shigella flexneri cell extract can be used for further studies on cancer therapy. [ABSTRACT FROM AUTHOR]

Endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), are a major cause of male infertility by disrupting spermatogenesis. Here, we examined the potential protective benefits of kaempferol (KMF), a flavonol known for its antioxidant properties, on BPA-induced reproductive toxicity in adult male rats. Human skin fibroblast cells (HNFF–P18) underwent cell viability assays. Thirty-five male Wistar rats were assigned to four groups: 1) control, 2) BPA (10 mg/kg), 3,4) BPA, and different dosages of KMF (1 and 10 mg/kg). The study examined the rats' testosterone serum level, antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD), oxidative markers malondialdehyde (MDA) and total antioxidant capacity (TAC), body weight, weight ratios of testis and prostate, and histopathological examinations. The study revealed that using KMF to treat rats exposed to BPA increased cell viability. Moreover, the rats' testosterone levels, which BPA reduced, showed a significant increase after KMF was included in the treatment regimen. Treatment with BPA led to oxidative stress and tissue damage, but simultaneous treatment with KMF restored the damaged tissue to its normal state. Histopathology studies on testis and prostate tissues showed that KMF had an ameliorative impact on BPA-induced tissue damage. The research suggests that KMF, a flavonol, could protect male rats from the harmful effects of BPA on reproductive health, highlighting its potential healing properties. • Kaempferol reduces oxidative stress caused by bisphenol A in the male reproduction system. • BPA is a major cause of male infertility by disrupting spermatogenesis. • Kaempferol improves male reproductive health. • Kaempferol significantly reduces testis and prostate injury caused by bisphenol A. [ABSTRACT FROM AUTHOR]

Chemotherapeutic nanoformulations, which can induce the immunogenic death of tumor cells, have attracted increasing attention for their abilities to enable and potentiate combination chemoimmunotherapy. Immunogenic cell death (ICD) causes the release of tumor-associated antigens, tumor-specific antigens, danger-associated molecular patterns, and pro-inflammatory cytokines, which trigger adaptive immune cells to elicit an antitumor immune response. The combination of ICD-inducing nanomedicines and immunoactivators represents a promising strategy for enhancing chemoimmunotherapy in clinical applications. In this review, we provide an overview of the latest advances in chemotherapeutic nanoformulation-mediated immune activation and the combination strategies with various immunoactivating agents, such as immune checkpoint inhibitors, indoleamine 2,3-dioxygenase inhibitors, cytokines, and Toll-like receptor agonists, and predict their potential to contribute significantly to clinical cancer chemoimmunotherapy.

Isatin (1H indole 2, 3-dione) is a heterocyclic, endogenous lead molecule recognized in humans and different plants. The isatin nucleus and its derivatives are owed the attention of researchers due to their diverse pharmacological activities such as anticancer, anti-TB, antifungal, antimicrobial, antioxidant, anti-inflammatory, anticonvulsant, anti-HIV, and so on. Many research chemists take advantage of the gentle structure of isatins, such as NH at position 1 and carbonyl functions at positions 2 and 3, for designing biologically active analogues via different approaches. Literature surveys based on reported preclinical, clinical, and patented details confirm the multitarget profile of isatin analogues and thus their importance in the field of medicinal chemistry as a potent chemotherapeutic agent. This review represents the recent development of isatin analogues possessing potential pharmacological action in the years 2016–2020. The structure–activity relationship is also discussed to provide a pharmacophoric pattern that may contribute in the future to the design and synthesis of potent and less toxic therapeutics.

l‐Asparaginase (E.C.3.5.1.1.) is a vital enzyme that hydrolyzes l‐asparagine to l‐aspartic acid and ammonia. This property of l‐asparaginase inhibits the protein synthesis in cancer cells, making l‐asparaginase a mainstay of pediatric chemotherapy practices to treat acute lymphoblastic leukemia (ALL) patients. l‐Asparaginase is also recognized as one of the important food processing agent. The removal of asparagine by l‐asparaginase leads to the reduction of acrylamide formation in fried food items. l‐Asparaginase is produced by various organisms including animals, plants, and microorganisms, however, only microorganisms that produce a substantial amount of this enzyme are of commercial significance. The commercial l‐asparaginase for healthcare applications is chiefly derived from Escherichia coli and Erwinia chrysanthemi. A high rate of hypersensitivity and adverse reactions limits the long‐term clinical use of l‐asparaginase. Present review provides thorough information on microbial l‐asparaginase bioprocess optimization including submerged fermentation and solid‐state fermentation for l‐asparaginase production, downstream purification, its characterization, and issues related to the clinical application including toxicity and hypersensitivity. Here, we have highlighted the bioprocess techniques that can produce improved and economically viable yields of l‐asparaginase from promising microbial sources in the current scenario where there is an urgent need for alternate l‐asparaginase with less adverse effects. [ABSTRACT FROM AUTHOR]

Docetaxel (DOCX) kills tumor cells through the formation of microtubules, calcium ion influx, apoptosis, and inflammation. However, DOCX has adverse effect on normal tissues through the production of reactive oxygen species (ROS), despite the adverse effect was inhibited by antioxidants. We investigated the protective role of selenium against DOCX-induced apoptosis and mitochondrial oxidative injury in laryngotracheal epithelial (LARYN) cells of mice. Thirty-two mice were divided into four groups (n = 8). The first group was used as a control. The second and third groups were treated with sodium selenite (Na-Sel) and DOCX, respectively. The fourth group was the combined group of Na-Sel and DOCX. At the end of the experiment, LARYN mucosa and cells were obtained from the mice. In the LARYN cells, the cell viability level was low in DOCX group, although glutathione peroxidase activity and cell viability level were increased by the treatment of Na-Sel. Increased lipid peroxidation, intracellular ROS, mitochondrial membrane depolarization, cell death levels, TNF-α, IL-1β, IL-6, caspase -3, and -9 activities in the DOCX group of LARYN cells were diminished by the treatment of Na-Sel. In conclusion, DOCX increased mitochondrial ROS, cell death, and inflammation in the LARYN cells, although the increase was reduced in the cells by Na-Sel treatment. DOCX-induced adverse oxidant, inflammatory, and apoptotic effects in the tissue might be reduced by the Na-Sel treatment. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate carnitine action against negative effects of etoposide on stem/progenitor spermatogonia and on sperm production. Carnitine (250 mg/kg body weight/day) and etoposide (5 mg/kg body weight/day) were administered from 25-days postpartum to 32-days postpartum. Testes were collected at 32-days postpartum, 64-days postpartum, and 127-days postpartum, and submitted to the immuno-labeling of UTF1, SOX2, and PLZF proteins to identify undifferentiated spermatogonia populations. At 127-days postpartum, sperm were collected for analysis. Carnitine+etoposide group showed a higher numerical density of spermatogonia labeled for all studied proteins at 64-days postpartum (critical age) compared to the etoposide group. Moreover, there was an improvement of spermatic parameters and sperm DNA integrity in rats of the carnitine+etoposide group in comparison with rats of the etoposide group. The results suggest that carnitine improves the self-renewal of undifferentiated spermatogonia and promotes a partial protection on them, alleviating the etoposide harmful late effects and leading to an enhancement of the sperm parameters in adulthood: [ABSTRACT FROM AUTHOR]

Introduction: Despite its importance in pre-chemotherapy counselling, specific reproductive toxicological information about cisplatin and paclitaxel is very rare. This study aimed to investigate the concentrations at which cisplatin and paclitaxel, alone or combined, affect the in vitro development of ovarian follicles. Their differential effects on the oocytes and surrounding granulosa cells was also evaluated.Material and Methods: Ovarian follicles were cultured in vitro using gonadotropins and treated with 10-8-10-10 M of cisplatin, paclitaxel, or both. At day 13, granulosa cells and oocytes were retrieved and used for imaging and functional analyses.Results: Follicular survival and growth was significantly suppressed in all treatment groups at 10-9 M or higher concentrations, and additive effects were observed in the combination group (p < 0.01). Oocyte-specific genes such as growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) were more suppressed in the paclitaxel group than in the cisplatin group. Granulosa cell-specific gene suppression and its electron microscopic alteration were more prominent in the cisplatin group than in the paclitaxel group. X-linked inhibitor of apoptosis protein (XIAP) expression of granulosa cells was also further down-regulated in the cisplatin group.Conclusions: These data provide an insight into the critical concentrations regarding in vitro follicular development and the differential effects of chemotherapeutic effects on oocytes and granulosa cells. Further studies are necessary to develop more efficient pre-chemotherapeutic fertility-sparing medical treatment that can evade oocyte-specific damage. [ABSTRACT FROM AUTHOR]

The advancement in therapy has provided a dramatic improvement in the rate of recovery among cancer patients. However, this improved survival is also associated with enhanced risks for cardiovascular manifestations, including hypertension, arrhythmias, and heart failure. The cardiotoxicity induced by chemotherapy is a life-threatening consequence that restricts the use of several chemotherapy drugs in clinical practice. This article addresses the prevalence of cardiotoxicity mediated by commonly used chemotherapeutic and immunotherapeutic agents. The role of susceptible genes and radiation therapy in the occurrence of cardiotoxicity is also reviewed. This review also emphasizes the protective role of antioxidants and future perspectives in anticancer drug-induced cardiotoxicities.

Chemotherapy-induced neutropenia (CIN) has been associated with a risk of infections and chemotherapy dose reductions and delays. The chemotherapy regimen remains one of the primary determinants of the risk of neutropenia, with some regimens being more myelotoxic than others. Although a number of clinical trials have currently highlighted the risk of CIN with each chemotherapy regimen, only a few ones have comprehensively examined the risk associated with all chemotherapeutic agents. Therefore, this study aimed to investigate the risk factors and characteristics of CIN caused by each neoplastic agent using data from the large voluntary reporting Food and Drug Administration Adverse Event Reporting System database. Initially, univariate analysis showed that an age ≥ 65 years, the female sex, and treatment with chemotherapeutic agents were factors that caused CIN. Then, cluster and component analyses showed that cytotoxic agents (i.e., alkylating agents, antimetabolic agents, antineoplastic antibiotics, platinating agents, and plant-derived alkaloids) were associated with infection following neutropenia. This comprehensive analysis comparing CIN risk suggests that elderly or underweight patients treated with cytotoxic drugs require particularly careful monitoring.

Myelotoxicity remains the most important cause of life threatening complications in patients undergoing antineoplastic chemotherapy cycles. Strategies to circumvent or lessen myelotoxicity may improve clinical outcome and quality of life in these patients. The aim of the present study is to investigate myeloprotective effect of Triticum aestivum Linn. (wheat) grass against chemotherapeutic agents induced bone marrow toxicity. Swiss albino mice were pretreated with wheatgrass juice at a dose of 20 ml/kg b.w. for 30 days. An hour after the last dose administration of WGJ, animals were injected with a single i.p. dose of cyclophosphamide (50 mg/kg b.w.) and doxorubicin (50 mg/kg b.w.). The reference drug amifostine (350 mg/kg b.w.) was administered 45 min prior to the cyclophosphamide and doxorubicin injection. At 24 h post chemotherapeutics challenge, animals were euthanized after blood sample collection and bone marrow was aspirated from both femurs. Hematologic parameters in blood samples were measured. Chromosomal abnormalities such as chromatid break, chromosomal ring, chromatid gap, chromatid exchange, chromosome break and number of micronucleated polymorphonuclear erythrocytes formed and polychromatic erythrocytes/normochromatic erythrocytes ratio were recorded in bone marrow smear. The results of present study show that pretreatment with wheatgrass juice significantly protected against cyclophosphamide and doxorubicin induced hematologic abnormalities and chromosomal damage in bone marrow stem cells due to its vast array of active principles. By virtue of its anticlastogenic and cytoprotective effects, wheatgrass juice might be considered as a promising candidate for adjuvant therapy without compromising efficacy of chemotherapeutic agents.

Despite substantial advancements in curative modern medicine in the last few decades, cancer risk and casualty rates have continued to mount globally. The exact reason for cancer's onset and progression is still unknown. However, skeletal and functional abnormalities in the genetic code are assumed to be the primary cause of cancer. Many lines of evidence reported that some medicinal plants can be utilized to curb cancer cell proliferation with a safe, fruitful, and cost-efficient perspective. Curcuminoid, isolated from Curcuma longa , have gotten a lot of focus due to their anticancer potential as they reduce tumor progression, invasion, and dissemination. Further, they modulated signal transduction routes like MAPK, PI3K/Akt/mTOR, JAK/STAT, and Wnt/β-catenin, etc., and triggered apoptosis as well as actuated autophagy in malignant cells without altering the normal cells, thus preventing cancer progression. Besides, Curcuminoid also regulate the function and expression of anti-tumor and carcinogenic miRNAs. Clinical studies also reported the therapeutic effect of Curcuminoid against various cancer through decreasing specific biomarkers like TNF-α, Bcl-2, COX-2, PGE2, VEGF, IκKβ, and various cytokines like IL-12p70, IL-10, IL-2, IFN-γ levels and increasing in p53 and Bax levels. Thus, in the present review, we abridged the modulation of several signal transduction routes by Curcuminoids in various malignancies, and its modulatory role in the initiation of tumor-suppressive miRNAs and suppression of the oncogenic miRNAs are explored. Additionally, various pharmacokinetic approaches have been projected to address the Curcuminoids bioavailability like the use of piperine as an adjuvant; nanotechnology- based Curcuminoids preparations utilizing Curcuminoids analogues are also discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The degradation of daunorubicin (DNR), doxorubicin (DXR) and vincristine (VCR) as chemotherapeutic agents was investigated under stress conditions such as acidic and alkaline media, oxidation, photolytic and heating. The degradation pathway determined by high-performance liquid chromatography (HPLC). Daunorubicin, doxorubicin and vincristine completely disintegrated in the basic medium. It has been determined that these drugs are resistant to heat. Daunorubicin and doxorubicin are resistant to UV light. However, vincristine is not very stable such as the other two compounds against UV light. The kinetic and thermodynamic parameters of daunorubicin, doxorubicin and vincristine were investigated in neutral media with different temperatures by electrochemical technique. Enthalpy, entropy and Gibbs free energy parameters were investigated in pH 7.4 phosphate buffer (PB) solution due to stability of these drugs at this pH. The studied chemotherapeutic agents showed endothermic process on glassy carbon-based electrode surface. Daunorubicin, doxorubicin and vincristine showed strongly adsorption process in room temperature. However, it showed diffusion property from electrode to solution with increasing the temperature values. [ABSTRACT FROM AUTHOR]

An all-in-one advanced nanoplatform was proposed toward chemo-photodynamic therapy with precisely controllable composition and drug loading content. Chemo-photodynamic therapy is an attractive strategy against cancer. However, the combination of chemotherapeutic agent and photosensitizer is usually realized by physically embedding one or two agents in the carriers. In this case, batch to batch variation of drug contents increases the risk of composition uncertainty, limiting the clinical application of currently developed chemo-photodynamic therapy. Therefore, it is highly desirable for constructing chemo-photodynamic therapy nanoplatform with precisely controllable composition and drug loading content. Here, a precise chemo-photodynamic therapy nanoplatform is reported based on the chemical conjugation of both doxorubicin (DOX) and photosensitizer chlorin e6 (Ce6) to active targeting hyaluronic acid (HA). The achieved HA-DOX-Ce6 (HDC) conjugate can self-assemble into all-in-one nanoparticles (NPs) with properties of pH-response, self-targeting delivery, near-infrared (NIR) fluorescence imaging and chemo-photodynamic combination therapy. Because HDC conjugate holds precise components, the HDC NPs have a constant composition and drug loading content, endowing a precise chemo-photodynamic therapy nanoplatform. The HDC NPs show significantly higher cellular uptake and remarkably better tumor-targeted accumulation than free drugs. Moreover, HDC NPs with the laser irradiation exhibit enhanced anticancer activities both in vitro and in vivo. This work may open the door for design of all-in-one advanced nanoplatform toward chemo-photodynamic therapy with precisely controllable composition and drug loading content. [ABSTRACT FROM AUTHOR]

Fas/CD95 plays a pivotal role in T cell-mediated cytotoxicity. Accumulating evidence has suggested that resistance to Fas-mediated apoptosis contributes to the escape of cancer cells from immune destruction, and allows to undergo proliferation and outgrowth of cancer cells. In this study, we found that the anti-cancer drug gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), has an ability to enhance Fas-mediated cytotoxicity. In the presence of nontoxic concentrations of gefitinib, Fas-induced activation of caspase-8 and subsequent apoptosis was dramatically promoted, suggesting that gefitinib increases the sensitivity to Fas-mediated apoptosis. Interestingly, the effects of gefitinib were observed in EGFR or p53 knockout (KO) cells. These observations indicate that both EGFR and p53 are dispensable for the enhancement. On the other hand, gefitinib clearly downregulated heat shock protein 70 (HSP70) as previously reported. Considering that HSP70 contributes to protection of cells against Fas-mediated apoptosis, gefitinib may increase the sensitivity to Fas-mediated apoptosis by downregulating HSP70. Thus, our findings reveal novel properties of gefitinib, which may provide insight into the alternative therapeutic approaches of gefitinib for Fas-resistant tumors. [ABSTRACT FROM AUTHOR]