Vity, and caused redox imbalance [81]. Collectively, molecular pathways-targets for MDR modulation by GSH controlling agents are schematically presented in Figure 3. 3.1.2. Overexpression of ABC Transporters: Effects of NADPHOxidase and CYP Inhibitors. NADPH-oxidase (NOX) is an oxidoreductase and plays Quizartinib web crucial roles in cell growth, proliferation, and regulation of phosphatases and transcription factors via redox-sensitive cysteine residues [82]. Elevated NOX expression has been shown in breast cancer [83], colon cancer [84], and neuroblastoma cells [85]. Barth et al. have demonstrated that pharmacological block of glucosylceramide synthase, a stimulator of NOX activity, substantially improved cytotoxicity of chemotherapeutics in Win 63843MedChemExpress Pleconaril glioblastoma cells [86]. The molecular mechanism of anticancer effects of cisplatin involves activation of Akt/mTOR pathway regulated by NOX-generated ROS, and NOX inhibition by diphenyl iodonium was critical for cisplatin cytotoxicity [87]. Overexpression of the drug and xenobiotic metabolising cytochrome P450 enzymes for a long time has been considered as one of the major mechanisms of chemoresistance in solid tumours [88, 89]. Types 1 and 2 CYPs have been proven to activate procarcinogens into ultimate carcinogens [90]. CYPs have become therapeutic targets in anticancer protocols amid their involvement in the activation and/or inactivation of chemotherapeutic drugs [91]. Molina-Ortiz et al. reported that altered CYP expression played a crucial role in the therapy of Rhabdomyosarcoma patients [92]. The in vitro antitumour action of natural product austocystin DOxidative Medicine and Cellular LongevityNADP+ NADP+NADPHNADPH NADPH CAT GR HOOH GSH GSSG GPx LOOH HOOH H2 O LOOH HOOH Prxox Prxred Trx red Trx ox NADPH TrxRFigure 3: Antioxidant and prooxidant systems as molecular targets for redox-active MDR modulators. Glutathione and enzymes involved in the glutathione metabolism such as glutathione reductase (GR) and glutathione peroxidase (Gpx) as well as gamma-glutamyl cysteine ligase, catalase, NADPH-oxidase, thioredoxin (Trx), and peroxiredoxins (Prx) are potential molecular targets for future MDR modulators.has been explained by selective activation of CYP enzymes leading to DNA damage [93]. 3.2. Chemotherapy-Induced Inflammatory Responses May Cause Redox-Regulated Multidrug Chemoresistance. To increase clinical efficacy of chemotherapy and combat MDR, molecular and cellular processes promoting inflammation have been targeted due to the common knowledge that (i) inflammatory cells are present within tumours and (ii) tumours arise at sites of chronic inflammation [94, 95]. Cancer promotion and progression stages are accelerated by ROS generated by immune cells, mediators of inflammation [96]. The induction of antioxidant defence enzymes in tumours as an adaptation to oxidative attacks from host immune cells might contribute to chemoresistance. Thus, hydrogen peroxide-resistant thymic lymphoma cells with increased catalase and total SOD activities, altered GSSG/ GSH redox potential, and oxidised NADP+ /NADPH pool exhibited resistance to conventional chemotherapeutics, such as cyclophosphamide, doxorubicin, vincristine, and glucocorticoids [97]. Chemotherapeutic agents caused release of ATP into the extracellular space as they induced tumour cell death [98]. Following accumulation of adenosine in tumours through CD39 and CD73, immune responses were suppressed [99]. Clayton et al. showed that exosomeexpressing CD39.Vity, and caused redox imbalance [81]. Collectively, molecular pathways-targets for MDR modulation by GSH controlling agents are schematically presented in Figure 3. 3.1.2. Overexpression of ABC Transporters: Effects of NADPHOxidase and CYP Inhibitors. NADPH-oxidase (NOX) is an oxidoreductase and plays crucial roles in cell growth, proliferation, and regulation of phosphatases and transcription factors via redox-sensitive cysteine residues [82]. Elevated NOX expression has been shown in breast cancer [83], colon cancer [84], and neuroblastoma cells [85]. Barth et al. have demonstrated that pharmacological block of glucosylceramide synthase, a stimulator of NOX activity, substantially improved cytotoxicity of chemotherapeutics in glioblastoma cells [86]. The molecular mechanism of anticancer effects of cisplatin involves activation of Akt/mTOR pathway regulated by NOX-generated ROS, and NOX inhibition by diphenyl iodonium was critical for cisplatin cytotoxicity [87]. Overexpression of the drug and xenobiotic metabolising cytochrome P450 enzymes for a long time has been considered as one of the major mechanisms of chemoresistance in solid tumours [88, 89]. Types 1 and 2 CYPs have been proven to activate procarcinogens into ultimate carcinogens [90]. CYPs have become therapeutic targets in anticancer protocols amid their involvement in the activation and/or inactivation of chemotherapeutic drugs [91]. Molina-Ortiz et al. reported that altered CYP expression played a crucial role in the therapy of Rhabdomyosarcoma patients [92]. The in vitro antitumour action of natural product austocystin DOxidative Medicine and Cellular LongevityNADP+ NADP+NADPHNADPH NADPH CAT GR HOOH GSH GSSG GPx LOOH HOOH H2 O LOOH HOOH Prxox Prxred Trx red Trx ox NADPH TrxRFigure 3: Antioxidant and prooxidant systems as molecular targets for redox-active MDR modulators. Glutathione and enzymes involved in the glutathione metabolism such as glutathione reductase (GR) and glutathione peroxidase (Gpx) as well as gamma-glutamyl cysteine ligase, catalase, NADPH-oxidase, thioredoxin (Trx), and peroxiredoxins (Prx) are potential molecular targets for future MDR modulators.has been explained by selective activation of CYP enzymes leading to DNA damage [93]. 3.2. Chemotherapy-Induced Inflammatory Responses May Cause Redox-Regulated Multidrug Chemoresistance. To increase clinical efficacy of chemotherapy and combat MDR, molecular and cellular processes promoting inflammation have been targeted due to the common knowledge that (i) inflammatory cells are present within tumours and (ii) tumours arise at sites of chronic inflammation [94, 95]. Cancer promotion and progression stages are accelerated by ROS generated by immune cells, mediators of inflammation [96]. The induction of antioxidant defence enzymes in tumours as an adaptation to oxidative attacks from host immune cells might contribute to chemoresistance. Thus, hydrogen peroxide-resistant thymic lymphoma cells with increased catalase and total SOD activities, altered GSSG/ GSH redox potential, and oxidised NADP+ /NADPH pool exhibited resistance to conventional chemotherapeutics, such as cyclophosphamide, doxorubicin, vincristine, and glucocorticoids [97]. Chemotherapeutic agents caused release of ATP into the extracellular space as they induced tumour cell death [98]. Following accumulation of adenosine in tumours through CD39 and CD73, immune responses were suppressed [99]. Clayton et al. showed that exosomeexpressing CD39.
