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Development and validation of a UHPLC-MS/MS method for the identification of irinotecan photodegradation products in water samples
2020
Gosetti, Fabio | Belay, Masho Hilawie | Marengo, Emilio | Robotti, Elisa
Irinotecan (CPT-11) is a water-soluble anticancer drug widely used to treat several types of cancer.Even if the metabolites of CPT-11 are well-known and investigated, only limited information is available in the literature about the formation of photo-degradation products that can naturally originate from sunlight irradiation when the drug is released in aqueous systems.CTP-11 solutions at 10.0 mg L−1 were irradiated by simulated sunlight. The intensity of the drug decreased by 90% after 7.5 days of irradiation and no significant reduction of absorbance values was observed after 13 days.A sensitive UHPLC-MS/MS method was developed employing a hybrid triple quadrupole/linear ion trap mass spectrometer, that is able to work in data-dependent acquisition mode and to obtain information about the compounds formed during the photoirradiation. Moreover, a selected reaction monitoring method was built using the MS/MS fragmentation pattern of the compounds previously investigated. The method was validated considering LOD, LOQ, linearity, precision, selectivity, recovery and matrix effect. LOD and LOQ values were 0.02 and 0.05 ng mL−1, respectively, whereas MDL and MQL values in real water samples (river water, groundwater, well water, and wastewater) were lower than 0.05 and 0.2 ng mL−1, respectively.Eight photodegradation products were identified, among which five for the first time. Based on the MS and MS/MS fragmentation, the chemical structures of the degradation products were proposed. Hydrolysis experiments were carried out on the same solutions preserved in the dark, but no formation of other species was highlighted.The method was applied to several real samples: CPT-11 was detected and quantified only in a hospital effluent sample at the concentration of 0.41 ± 0.2 ng mL−1 together with the occurrence of PDP3.The outcomes of this study may be useful for updating the pollutant screening in water samples.
Показать больше [+] Меньше [-]Resveratrol prevents benzo(a)pyrene-induced disruption of mitochondrial homeostasis via the AMPK signaling pathway in primary cultured neurons
2020
Kang, Run-Run | Sun, Qian | Chen, Kai-Ge | Cao, Qing-Tian | Liu, Chang | Liu, Kuan | Ma, Zhuo | Deng, Yu | Liu, Wei | Xu, Bin
Exposure to benzo(a)pyrene (BaP) has been shown to cause mitochondrial dysfunction and injury to neural cells. Resveratrol (RSV) has been studied as an antioxidant, anti-inflammatory, anti-apoptotic, and anticancer agent and can modulate mitochondrial function in vitro and in vivo. However, the molecular mechanisms underlying RSV’s protection against mitochondrial dysfunction have not been fully elucidated. To investigate whether RSV can effectively prevent BaP-induced mitochondrial dysfunction, we tested the effects of RSV in primary neuronal models. Our results confirmed that neurons exhibited mitochondrial dysfunction and apoptosis in the mitochondrial pathway after BaP-treatment, and that pretreatment with RSV could reduce that dysfunction. Further, our results indicated that RSV pretreatment enhanced mitochondrial biogenesis via the AMPK/PGC-1α pathway and activated mitophagy via the PINK1-Parkin and AMPK/ULK1 pathways, thereby coordinating mitochondrial homeostasis. We also found that RSV could alleviate mitochondrial network fragmentation caused by BaP. This work provided insights into the role of RSV in preventing BaP-induced primary neuronal apoptosis in the mitochondrial pathway, mainly via regulation of mitochondrial biogenesis and mitophagy through AMPK pathway, thus maintaining the integrity of the mitochondrial network.
Показать больше [+] Меньше [-]Synthetic phenolic antioxidant propyl gallate induces male infertility through disruption of calcium homeostasis and mitochondrial function
2019
Ham, Jiyeon | Lim, Whasun | Park, Sunwoo | Bae, Hyocheol | You, Seungkwon | Song, Gwonhwa
Propyl gallate (propyl 3,4,5-trihydroxybenzoate, PG) is a phenolic antioxidant that has been used for oil-containing foods to prevent acidification. Owing to its antioxidant properties, PG has been applied to various fields and active research is currently underway to prove PG as an anticancer agent. However, there are still concerns about PG as a possible reproductive toxicant. Therefore, we determined whether PG induced male infertility. Our results indicated that PG induced testicular dysfunction in both Leydig and Sertoli cells via suppression of cell viability and steroidogenesis. These normal testis functions were destroyed by PG-induced mitochondrial dysfunction and calcium homeostasis dysregulation. In addition, PG disrupted the expression of several genes associated with the testis function and induced endoplasmic reticulum stress. Furthermore, we verified PG-induced mRNA expression changes in steroidogenesis enzymes and hormone receptors in vitro and in vivo. From the results of the qPCR analysis, we further confirmed the PG-mediated reduction in the mRNA expression of genes related to testis functions by in situ hybridization. Finally, we demonstrated that PG induced testicular toxicity via the disruption of mitochondrial or ER function and the inhibition of testicular development-related genes in mice.
Показать больше [+] Меньше [-]Anticancer drugs: Consumption trends in Spain, prediction of environmental concentrations and potential risks
2017
Franquet-Griell, Helena | Gómez-Canela, Cristian | Ventura, Francesc | Lacorte, Silvia
This study presents the occurrence and impact of 78 anticancer drugs compounds in Spanish river basins based on consumption data during the period 2010–2015 and calculation of the predicted environmental concentrations (PEC). The total consumption of anticancer drugs in Spanish pharmacies was of 23.4 tons in 2015, being mycophenolic acid and hydroxycarbamide the drugs with the highest prescription. Their PECs in river at national scale were up to 80 ng/L. However, the use of different dilution factors revealed major differences between hydrographic basins, and PECriver rose up to 68,014 ng/L in highly populated rivers with low flows. Concerning acute toxicity, there was no expected risk for the aquatic environment. However, chronic toxicity tests revealed possible long-term mutagenic effects for aquatic organisms. This study provides the tools for the estimation of PEC at river basin scale using time trend consumption data compilation. This information is very useful for prioritization of compounds of concern and permit to focus resources in environmental monitoring and risk evaluation.
Показать больше [+] Меньше [-]Magnetic nanoparticles based on cerium MOF supported on the MWCNT as a fluorescence quenching sensor for determination of 6-mercaptopurine
2022
Ashrafzadeh Afshar, Elham | Taher, Mohammad Ali | Karimi-Maleh, Hassan | Karaman, Ceren | Joo, Sang-Woo | Vasseghian, Yasser
In this study, a new magnetic nanocomposite was developed as an efficient and fast-response fluorescence quenching sensor for determination of anticancer drug 6-mercaptopurine (6-MP). For this purpose, the needle-shape fluorescence metal-organic framework of cerium (Ce-MOF) were successfully synthesized on the surface of multiwalled carbon nanotubes using 1,3,5-benzenetricarboxylic acid ligand via a facile solvothermal assisted route and magnetized. The accuracy of the proposed synthesis was confirmed using the FT-IR, FE-SEM, XRD, and VSM methods. The obtained product as presented the fluorescence emission in 331 nm by excitation of 293 nm in excitation/emission slit widths of 10.0 nm. The operation of suggested method is based on quenching the fluorescence signal in accordance with increasing the 6-MP concentration. The proposed assay effectively detected the trace amount of 6-MP in the linear range of 1.0 × 10⁻⁶ to 7 × 10⁻⁵ M. The limit of detection and limit of quantification were obtained as 8.6 × 10⁻⁷ and 2.86 × 10⁻⁶ M, respectively. The analyte molecule was determined in real samples with satisfactory recoveries between 98.75 and 105.33.
Показать больше [+] Меньше [-]Cytotoxicity, in vivo toxicity, and chemical composition of the hexane extract of Plectranthus amboinicus (Lour.) Spreng
2021
Almalki, Ahmed | Abutaha, Nael | Al-Doaiss, Amin A. | Mohammed, Al-Zahrani | Wadaan, Muhammad A.
Cancer is a universal health issue, and many anticancer therapeutic drugs have been isolated from natural products. This study analyzed the cytotoxic and apoptotic activity of Plectranthus amboinicus leaf hexane (PALH) extract in MDA-MB-231 (median inhibitory concentration [IC₅₀] = 39.26 μg/mL) and MCF7 (IC₅₀ = 89.05 μg/mL) breast cancer cell lines. Cells appeared rounded and shrunken, indicating morphological changes due to apoptosis induction. The primary constituent of PALH was phenol, 5-methyl-2-(1-methylethyl) (44%). PALH extract treatment increased the percentage of late apoptotic cells in the MDA-MB231 cell line (58% ± 1.5% at 200 μg/mL) compared to the control group, as evidenced by the activated caspase-3 and caspase-7 identified and captured by fluorescence microscopy. The relative migration rate in MDA-MB-231 cells treated with 10 μg/mL of PALH extract for 48 h was significantly lower compared to the control group. Analysis of acute (2000 mg/kg/BW) and subacute (250 and 500 mg/kg/BW) toxicity of PALH extract in mice showed no mortality or adverse effects in the kidney and liver histology compared to the control group. PALH extract can be considered nontoxic as it does not cause any adverse changes and so can be proposed as a potential breast anticancer agent.
Показать больше [+] Меньше [-]Role of multidrug resistance-associated proteins in cancer therapeutics: past, present, and future perspectives
2021
Elfadadny, Ahmed | El-Husseiny, Hussein M. | Abugomaa, Amira | Ragab, Rokaia F. | Mady, Eman A. | Aboubakr, Mohamed | Samir, Haney | Mandour, Ahmed S. | El-Mleeh, Amany | El-Far, Ali H. | Abd El-Aziz, Ayman H. | Elbadawy, Mohamed
Cancer, a major public health problem, is one of the world’s top leading causes of death. Common treatments for cancer include cytotoxic chemotherapy, surgery, targeted drugs, endocrine therapy, and immunotherapy. However, despite the outstanding achievements in cancer therapies during the last years, resistance to conventional chemotherapeutic agents and new targeted drugs is still the major challenge. In the present review, we explain the different mechanisms involved in cancer therapy and the detailed outlines of cancer drug resistance regarding multidrug resistance-associated proteins (MRPs) and their role in treatment failures by common chemotherapeutic agents. Further, different modulators of MRPs are presented. Finally, we outlined the models used to analyze MRP transporters and proposed a future impact that may set up a base or pave the way for many researchers to investigate the cancer MRP further.
Показать больше [+] Меньше [-]Fluorene-9-bisphenol inhibits epithelial-mesenchymal transition of human endometrial cancer Ishikawa cells by repressing TGF-β signaling pathway
2019
Wang, Lingjuan | Zhuang, Taifeng | Li, Fangzhou | Wei, Wei
Fluorene-9-bisphenol (BHPF), a new derivative of bisphenol A (BPA), has been introduced for treatment with estrogen-related tumors, such as endometrial cancer. This study investigated the potential mechanism underlying the action of BHPF against endometrial cancer in vitro. We used the cell counting kit-8 (CCK8) method on Ishikawa cells to screen sub-lethal doses of BHPF and established the optimal concentration at which BHPF influenced the proliferation of Ishikawa cells. Effect of BHPF on cell migration and invasion was investigated by cell scratch assay and transwell assay, respectively. Expression levels of epithelial-mesenchymal transition (EMT)–related proteins were detected by Western blot analysis. BHPF was found to inhibit the proliferation of Ishikawa cells, whose migration and invasion abilities were also reduced. Western blot indicated that BHPF can significantly inhibit the EMT process of Ishikawa cells by blocking transforming growth factor-β (TGF-β) signaling pathway. This is the first report of the effect of BHPF on the biological behavior of endometrial cancer cells and its inhibition of endometrial cancer progression by repressing both endometrial cell proliferation and epithelial-mesenchymal transition, hence suggesting it as a novel anti-cancer drug. Graphical abstract Schematic representation of the molecular basis underlying BHPF treatment. BHPF repressed the EMT process by regulating EMT-related genes, such as E-cadherin, N-cadherin, and vimentin as well as the TGF-β signaling pathway–related genes, including p-Smad2/3 and slug, in a BHPF-dependent manner.
Показать больше [+] Меньше [-]Plant asparaginase versus microbial asparaginase as anticancer agent
2022
Al-Hazmi, Nawal E. | Naguib, Deyala M.
The considerable effect of enzymes on human health draws great attention to enzyme-based drugs (therapeutic enzymes), in recent times. L-asparaginase (ASNase) is a well-known therapeutic enzyme. It has varied applications and is a single molecule for the treatment of multiple diseases. This study tries to extract asparaginase from soybean debris (agricultural wastes) as a cheap plant source and compare this with microbial asparaginase as an agent in cancer chemotherapy. The asparaginase was extracted and purified from soybean debris (plant asparaginase) and Pseudomonas aeruginosa (microbial asparaginase), then the physiochemical characters were determined for the two enzymes, and the anticancer activity of plant and microbial asparaginase was determined against gastric cancer (CLS-145), pancreatic cancer (AsPC-1), colon cancer (HCT116), esophagus cancer (KYSE-410), liver cancer (HepG2), breast cancer (MCF-7), and cervical cancer (HELLA). The results showed that plant asparaginase was superior to microbial asparaginase in its physiochemical characters. Plant asparaginase showed higher stability and activity under the conditions of changing either the temperature or the pH; also plant asparaginase has a higher affinity to the asparagine than the microbial asparaginase; besides, this plant asparaginase did not show activity with glutamine as a substrate. The plant asparaginase showed higher anticancer activity than that of microbial asparaginase against all studied cancer cell lines. The present study introduces as the first time a comparative study between the plant and microbial asparaginase which proves that soybean debris asparaginase can be more efficient and safe than that of the microbial asparaginase as an anticancer agent.
Показать больше [+] Меньше [-]Comprehensive review on naringenin and naringin polyphenols as a potent anticancer agent
2022
Rauf, Abdur | Shariati, Mohammad Ali | Imran, Muhammad | Bashir, Kashif | K̲h̲ān, Shāhid ʻAlī | Mitra, Saikat | Emran, Talha Bin | Badalova, Kamala | Uddin, Md Sahab | Mubarak, Mohammad S. | Aljohani, Abdullah S. M. | Alhumaydhi, Fahad A. | Derkho, Marina | Korpayev, Serdar | Zengin, Gokhan
Though the incidence of several cancers in Western societies is regulated wisely, some cancers such as breast, lung, and colorectal cancer are currently rising in many low- and middle-income countries due to increased risk factors triggered by societal and development problems. Surgery, chemotherapy, hormone, radiation, and targeted therapies are examples of traditional cancer treatment approaches. However, multiple short- and long-term adverse effects may also significantly affect patient prognosis depending on treatment-associated clinical factors. More and more research has been carried out to find new therapeutic agents in natural products, among which the bioactive compounds derived from plants have been increasingly studied. Naringin and naringenin are abundantly found in citrus fruits, such as oranges and grapefruits. A variety of cell signaling pathways mediates their anti-carcinogenic properties. Naringin and naringenin were also documented to overcome multidrug resistance, one of the major challenges to clinical practice due to multiple defense mechanisms in cancer. The effective parameters underlying the anticancer effects of naringenin and naringin include GSK3β inactivation, suppression of the gene and protein activation of NF-kB and COX-2, JAK2/STAT3 downregulation, downregulation of intracellular adhesion molecules-1, upregulation of Notch1 and tyrocite-specific genes, and activation of p38/MAPK and caspase-3. Thus, this review outlines the potential of naringin and naringenin in managing different types of cancers.
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