Contribution of tumoral and host solute carriers to clinical drug response

Sprowl, Jason A.; Mikkelsen, Torben Stamm; Giovinazzo, Hugh; Sparreboom, Alex

doi:10.1016/j.drup.2012.01.009

Cited by 27 publications

(21 citation statements)

References 307 publications

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“…The mechanism of cellular uptake of cisplatin in tumor cells is not entirely clear and may vary from one cell type to another (28). Nonetheless, the current knowledge as to the role of carrier-mediated platinum transport has been reviewed in great detail (29, 30).…”

Section: Discussionmentioning

confidence: 99%

Modulation of OATP1B-Type Transporter Function Alters Cellular Uptake and Disposition of Platinum Chemotherapeutics

Lancaster

Sprowl

Walker

et al. 2013

Molecular Cancer Therapeutics

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Expression of the human organic anion transporting polypeptides OATP1B1 and OATP1B3 have been previously believed to be restricted to hepatocytes. Here we demonstrate that the gene encoding OATP1B3, but not OATP1B1, is abundantly expressed in multiple human solid tumors that include hepatocellular, lung, and ovarian carcinomas. Surprisingly, OATP1B3 expression in a panel of 60 human tumor cell lines was linked with sensitivity to multiple cytotoxic agents, including the platinum anticancer drugs cisplatin, carboplatin, and oxaliplatin. In addition, overexpression of OATP1B3 in mammalian cells increased cellular accumulation of platinum agents and decreased cell survival. In mice with a targeted disruption of the ortholog transporter Oatp1b2, the liver-to-plasma ratio of cisplatin was significantly reduced compared with wildtype mice, without concurrent changes in expression profiles of other transporter genes. Our findings indicate an unexpected role for tumoral and host OATP1B-type carriers in the toxicity and disposition of platinum anticancer drugs, and may provide a foundation for understanding the extensive interindividual pharmacodynamic variability seen with these drugs in patients.

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Section: Discussionmentioning

confidence: 99%

Modulation of OATP1B-Type Transporter Function Alters Cellular Uptake and Disposition of Platinum Chemotherapeutics

Lancaster

Sprowl

Walker

et al. 2013

Molecular Cancer Therapeutics

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“…(39,41) Interesting, the intracellular uptake of these drugs are also mediated by the nucleotide transporter proteins hENT1, hCNT1, and hCNT3. (42,43) So far, recombinant IFN-β has not yet been approved for the treatment of any cancer type and has yet to be clinically tested in pancreatic cancer. In addition, it is recommended to study the combination of IFN-β with the new developed chemotherapeutic agents such as FOLFIRINOX and Nab-Paclitaxel as well.…”

Section: Discussionmentioning

confidence: 99%

Interferon-beta enhances sensitivity to gemcitabine in pancreatic cancer

Blaauboer

Booy

Koetsveld

et al. 2020

Preprint

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Background: Adjuvant gemcitabine for pancreatic cancer has limited efficacy in the clinical setting. Impaired drug metabolism is associated with treatment resistance. We aimed to evaluate the chemosensitising effect of interferon-beta (IFN-β).Methods: BxPC-3, CFPAC-1, and Panc-1 cells were pre-treated with IFN-β followed by gemcitabine monotherapy. The effect on cell growth, colony formation, and cell cycle was determined. RT-qPCR was used to measure gene expression. BxPC-3 cells were used in a heterotopic subcutaneous mouse model. Results: IFN-β increased sensitivity to gemcitabine (4-, 7.7-, and 1.7-fold EC50 decrease in BxPC-3, CFPAC-1, and Panc-1, respectively; all P<0.001). Findings were confirmed when assessing colony formation. The percentage of cells in the S-phase was significantly increased after IFN-β treatment only in BxPC-3 and CFPAC-1 by 12% and 7%, respectively (p<0.001 and p<0.05, respectively). Thereby, IFN-β upregulated expression of the drug transporters SLC28A1 in BxPC-3 (252%) and SLC28A3 in BxPC-3 (127%) and CFPAC-1 (223%) (all p<0.001). In vivo, combination therapy reduced tumor volume with 45% (P=0.01). Both ex vivo and in vivo data demonstrate a significant reduction in the number of proliferating cells, whereas apoptosis was increased. Conclusions: For the first time, we validated the chemosensitising effects of IFN-β when combined with gemcitabine in vitro, ex vivo, and in vivo. This was driven by cell cycle modulation and associated with an upregulation of genes involving intracellular uptake of gemcitabine. The use of IFN-β in combination with gemcitabine seems promising in patients with pancreatic cancer and needs to be further explored.

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“…The pathogenesis and drug resistance of tumors are both associated with the abnormal expression of genes of the SLC superfamily, such as in liver cancer, colorectal cancer, and ovarian cancer [23][24][25]. Amino acid transporter proteins such as LAT1 affect the differentiation of T cells by regulating the activity of mTOR [22], and it has thus been used as a diagnostic and treatment target in prostate cancer [26].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Function of SLC7A7 in T-Cell Acute Lymphoblastic Leukemia

Yang

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Y+LAT1 protein, encoded by the SLC7A7 gene (a member of the SLC7 family), forms the cationic amino acid transport system y+L (system y+L). This system transports cationic amino acids such as arginine and lysine out of the cell. Arginine, in particular, is critical for T-cell activation and function in the immune response. Methods: We analyzed the role of the SLC7A7 gene in the cellular activities of Jurkat cells, specifically the cell cycle and cell proliferation, apoptosis, migration, and invasion. Cell proliferation was assessed using the Cell Counting Kit-8. Apoptosis and the cell cycle were determined with a FACSCalibur flow cytometer. A Transwell chamber was used to measure cell invasion and migration. Results: The proliferative ability of Jurkat cells was not significantly altered by transfection with SLC7A7 overexpression vectors. However, SLC7A7 overexpression significantly decreased the percentage of apoptotic Jurkat cells (P = 0.007) but significantly increased the proportion of G1 phase cells (P = 0.029) and cell migration (P < 0.001) and invasion (P < 0.001). Knockdown of SLC7A7 increased the cell apoptosis rate (P = 0.006) but decreased the G1 phase ratio (P = 0.002) and cell migration (P < 0.001) and invasion (P < 0.001). Conclusions: SLC7A7 plays a significant role in the pathogenesis of T-cell acute lymphoblastic leukemia.

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Contribution of tumoral and host solute carriers to clinical drug response

Cited by 27 publications

References 307 publications

Modulation of OATP1B-Type Transporter Function Alters Cellular Uptake and Disposition of Platinum Chemotherapeutics

Modulation of OATP1B-Type Transporter Function Alters Cellular Uptake and Disposition of Platinum Chemotherapeutics

Interferon-beta enhances sensitivity to gemcitabine in pancreatic cancer

Function of SLC7A7 in T-Cell Acute Lymphoblastic Leukemia

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