Uptake of Compounds That Selectively Kill Multidrug-Resistant Cells: The Copper Transporter<i>SLC31A1</i>(CTR1) Increases Cellular Accumulation of the Thiosemicarbazone NSC73306

Fung, King Leung; Tepede, Abisola K.; Pluchino, Kristen M.; Pouliot, Lynn M.; Pixley, Jessica N.; Hall, Matthew D.; Gottesman, Michael M.

doi:10.1021/mp500114e

Cited by 15 publications

(9 citation statements)

References 52 publications

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“…To the best of our knowledge, CTR1 has been found to regulate platinum drug uptake, such as cisplatin (35,36). However, there was no significant difference in the expression of CTR1 between SKOV3 and SKOV3/DDP cells.…”

Section: Discussionmentioning

confidence: 99%

Tolerance to endoplasmic reticulum stress mediates cisplatin resistance in human ovarian cancer cells by maintaining endoplasmic reticulum and mitochondrial homeostasis

Wang

et al. 2015

Oncology Reports

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The mechanism of cisplatin resistance in ovarian cancer is not fully understood. In the present study, we showed a critical role for endoplasmic reticulum (ER) stress tolerance in mediating cisplatin resistance in human ovarian cancer cells. We found cisplatin to inhibit the proliferation of two ovarian cancer cell lines: cisplatin-sensitive SKOV3 cells and cisplatin‑resistant SKOV3/DDP cells. However, the effect was greater in the cisplatin-sensitive SKOV3 cells. Cisplatin treatment induced ER stress in the SKOV3 cells but not in the SKOV3/DDP cells. Cisplatin-induced Ca2+ flow from the ER into mitochondria caused mitochondrial calcium overload, which amplified proapoptotic signaling in the cisplatin-sensitive SKOV3 cells. ER stress-mediated apoptosis and mitochondrial pathway-dependent apoptosis were induced in the cisplatin-sensitive SKOV3 cells, but not in the cisplatin-resistant SKOV3/DDP cells. Moreover, there were more ER-mitochondria contacts in the cisplatin-treated SKOV3 cells. Collectively, our data indicated that tolerance to cisplatin-induced ER stress inhibits ER stress-mediated apoptosis, prevents an imbalance in ER and mitochondrial calcium homeostasis and maintains cell survival, thus leading to cisplatin resistance in ovarian cancer cells.

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Section: Discussionmentioning

confidence: 99%

Tolerance to endoplasmic reticulum stress mediates cisplatin resistance in human ovarian cancer cells by maintaining endoplasmic reticulum and mitochondrial homeostasis

Wang

et al. 2015

Oncology Reports

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“…Total protein extraction from cell culture and protein concentration estimation methods was reported previously (Fung et al, 2014b). For SDS-PAGE, protein samples were loaded onto a 3-8% Tris-acetate gel (Invitrogen).…”

Section: Chemicals [mentioning

confidence: 99%

Tariquidar Is an Inhibitor and Not a Substrate of Human and Mouse P-glycoprotein

Weidner

Fung

Kannan

et al. 2015

Drug Metabolism and Disposition

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Since its development, tariquidar (TQR; XR9576;4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]carbamoyl]-4,5-dimethoxyphenyl]quinoline-3-carboxamide) has been widely regarded as one of the more potent inhibitors of P-glycoprotein (P-gp), an efflux transporter of the ATP-binding cassette (ABC) transporter family. A third-generation inhibitor, TQR exhibits high affinity for P-gp, although it is also a substrate of another ABC transporter, breast cancer resistance protein (BCRP). Recently, several studies have questioned the mechanism by which TQR interfaces with P-gp, suggesting that TQR is a substrate for P-gp instead of a noncompetitive inhibitor. We investigated TQR and its interaction with human and mouse P-gp to determine if TQR is a substrate of P-gp in vitro. To address these questions, we used multiple in vitro transporter assays, including cytotoxicity, flow cytometry, accumulation, ATPase, and transwell assays. A newly generated BCRP cell line was used as a positive control that demonstrates TQR-mediated transport. Based on our results, we conclude that TQR is a potent inhibitor of both human and mouse P-gp and shows no signs of being a substrate at the concentrations tested. These in vitro data further support our position that the in vivo uptake of [ 11 C]TQR into the brain can be explained by its highaffinity binding to P-gp and by it being a substrate of BCRP, followed by amplification of the brain signal by ionic trapping in acidic lysosomes.

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“…These facts reflect the important role that coordination to Fe and Cu plays in the biological activity of TSCs. In this sense, it has been demonstrated that lysosomal apoptotic pathway in cancer cells is activated through copper sequestration by thiosemicarbazones [66][67][68][69], while the copper transporter 1 protein (CTR1) increases the thiosemicarbazone uptake by cisplatin-resistant cell lines [70]. In a recently published study on the cytotoxicity of thiosemicarbazones, the addition of Cu II ions has been found to inactivate 3-aminopyridine-2-carbaldehyde thiosemicarbazone (Triapine ® ) while increases the activity of di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mt) [71,72] and bis-thiosemicarbazonato ligands [73].…”

Section: -Introductionmentioning

confidence: 99%

Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines

García–Tojal

Gil‐García

Fouz

et al. 2018

Journal of Inorganic Biochemistry

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Thiosemicarbazones (TSCs), and their copper derivatives, have been extensively studied mainly due to the potential applications as antitumor compounds. A part of the biological activity of the TSC-Cu complexes rests on their reactivity against cell reductants, as glutathione (GSH). The present paper describes the structure of the [Cu(PTSC)(ONO)] compound (1) (HPTSC=pyridine-2-carbaldehyde thiosemicarbazone) and its spectroscopic and magnetic properties. ESI studies performed on the reaction of GSH with 1 and the analogous [{Cu(PTSC*)(ONO)}] derivative (2, HPTSC*=pyridine-2-carbaldehyde 4N-methylthiosemicarbazone) show the absence of peaks related with TSC-Cu-GSH species. However GSH-Cu ones are detected, in good agreement with the release of Cu ions after reduction in the experimental conditions. The reactivity of 1 and 2 with cytochrome c and myoglobin and their activities against HT-29 and SW-480 colon carcinoma cell lines are compared with those shown by the free HPTSC and HPTSC* ligands.

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Uptake of Compounds That Selectively Kill Multidrug-Resistant Cells: The Copper TransporterSLC31A1(CTR1) Increases Cellular Accumulation of the Thiosemicarbazone NSC73306

Cited by 15 publications

References 52 publications

Tolerance to endoplasmic reticulum stress mediates cisplatin resistance in human ovarian cancer cells by maintaining endoplasmic reticulum and mitochondrial homeostasis

Tolerance to endoplasmic reticulum stress mediates cisplatin resistance in human ovarian cancer cells by maintaining endoplasmic reticulum and mitochondrial homeostasis

Tariquidar Is an Inhibitor and Not a Substrate of Human and Mouse P-glycoprotein

Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines

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