P-glycoprotein depresses cisplatin sensitivity in L1210 cells by inhibiting cisplatin-induced caspase-3 activation

Gibalová, Lenka; Šereš, Mário; Rusnak, Andrej; Ditte, Peter; Labudová, Martina; Uhrík, B; Pastorek, Jaromı́r; Sedlák, J; Breier, Albert; Sulová, Zdena

doi:10.1016/j.tiv.2012.01.014

Cited by 53 publications

(50 citation statements)

References 41 publications

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“…P-gp-induced partial loss of L1210 cell sensitivity to cisPt was associated with deregulation of mitochondrial apoptotic pathway. This was connected with depression in caspase-3 activation in Pgp-positive R and T cells (Gibalova et al 2012). Differences in apoptotic progression in P-gp positive L1210 cells may be partially involved in resistance of these cells also to TNM.…”

Section: Discussionmentioning

confidence: 87%

“…In contrast, P-gppositive human AML cells (SKM-1/VCR, SKM-1/LEN and MOLM-13/VRC) are slightly more sensitive to cisPt (Table 1), which is not a P-gp substrate (Gibalova et al 2012). Interestingly, P-gp-positive L1210 cell variants L1210/R and L1210/T were two times less sensitive to latter anticancer drugs than P-gp-negative counterpart (Table 1).…”

Section: Characterization Of L1210 Skm-1 and Molm-13 Mdr Variantsmentioning

confidence: 98%

“…The main evidence for this assumption is the fact that a transport-defective P-gp mutant expressed in CEM lymphoma cells decreases apoptosis progression induced by vincristine (VCR) (Tainton et al 2004). Moreover, we have described less pronounced apoptosis progression induced by cisplatin (cisPt, not a P-gp substrate) in two P-gp-positive mouse leukemia cell variants, obtained either by selection with VCR (L1210/R) or by transfection with the human gene encoding P-gp (L1210/T) when compared with P-gp-negative parental L1210 cells (Gibalova et al , 2012. This additional role enables P-gp to reduce cell sensitivity to some drugs that are not P-gp substrates up to several times (Messingerova et al 2016).…”

Section: Introductionmentioning

confidence: 98%

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The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin

Pavlíková

Šereš²,

Imrichova³

et al. 2016

gpb

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Abstract. In P-gp-positive cell variants obtained from L1210 cells either by selection with vincristine (L1210/R) or by transfection with the human gene encoding P-gp (L1210/T), we have previously described cross-resistance to tunicamycin (TNM), a protein N-glycosylation inhibitor. Here we studied whether this cross-resistance also underlies P-gp-positive variants of human acute myeloid leukemia cells (AML) derived from SKM-1 and MOLM-13 cells (SKM-1/VCR, SKM-1/LEN, MOLM-13/ VCR) by selection with vincristine (VCR) and lenalidomide (LEN). While SKM-1/LEN cells were P-gp positive, no P-gp was detected in MOLM-13/LEN cells. P-gp-positive cells could be repeatedly passaged in medium containing TNM. In contrast, more than 90% of P-gp-negative cells were entering and progressing through cell death mechanisms after the third passage in medium containing TNM. Combined apoptosis/necrosis cell death was detected in L1210 cells after exposure to TNM. Passaging of P-gp-negative AML cells in medium containing TNM induced preferentially apoptosis. Damage to P-gp-negative cells induced with TNM was associated with arrest in the G1 phase of the cell cycle. P-gp-positive leukemia cells differed from P-gp-negative cells in the composition of plasma membrane glycoproteins, which we monitored with the aid of different lectins. The application of TNM to cells induced additional changes in membrane-linked glycosides.

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Section: Discussionmentioning

confidence: 87%

Section: Characterization Of L1210 Skm-1 and Molm-13 Mdr Variantsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

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The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin

Pavlíková

Šereš²,

Imrichova³

et al. 2016

gpb

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“…In addition, limiting GCS activity by either GCS siRNA/shRNA transfection or PPMP treatment downregulates P-gp expression and restores the ceramide-mediated death cascade, thereby heightening chemosensitivity in cisplatin-resistant HNC cells. Although cisplatin is a substance that is untransportable by P-gp, the sensitivity of cisplatin is affected by P-gp expression via inhibition cisplatininduced apoptosis without any contribution the drug efflux activity of P-gp (32). GCS blockade downregulates P-gp and restores p53-dependent apoptosis in chemoresistant cancer cells (18,19).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Glucosylceramide Synthase Sensitizes Head and Neck Cancer to Cisplatin

Roh

Kim

Park

et al. 2015

Molecular Cancer Therapeutics

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Glucosylceramide synthase (GCS) overexpression is associated with multidrug resistance in several human cancers. GCS blockade, which overcomes multidrug resistance by downregulating P-glycoprotein (P-gp), has not been tested in head and neck cancer (HNC). This study investigates whether GCS is targetable in HNC by assessing whether GCS inhibition sensitizes HNC to cisplatin. The effect of genetic or pharmacologic GCS inhibition (using GCS siRNA/shRNA or D,L-threo-PPMP, respectively) on cisplatin sensitivity was assessed in several human HNC cells and acquired cisplatin-resistant HNC cells by measuring cell viability, cell cycle, death, mRNA and protein expression, ceramide production, and in preclinical tumor xenograft mouse models. GCS and P-gp expression were significantly associated with cisplatin resistance in several HNC cell lines (P ¼ 0.007). Both were significantly increased in HN9-cisR cells, which display acquired cisplatin resistance (P < 0.001). Genetic or pharmacologic inhibition of GCS induced accumulation of increased ceramide levels. GCS inhibition increased cisplatin-induced cell death in HNC cells via P-gp downregulation and proapoptotic protein activation, which were abrogated by siPUMA transfection. Genetic and pharmacologic GCS inhibition sensitized resistant HNC cells to cisplatin in vitro and in vivo. GCS and P-gp overexpression is associated with acquired cisplatin resistance, suggesting a role for these molecules as therapeutic targets for HNC. Genetic or pharmacologic GCS blockade may have therapeutic benefit in cisplatin-resistant HNC.

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“…Besides this generally accepted role as a drug transporter, this protein may also play another role as an antiapoptotic regulatory protein and this role is independent of P-gp efflux activity [29,32]. This additional role also enables P-gp to reduce cell sensitivity to substances that are not its substrates, such as cisplatin several times [33,34].…”

Section: IImentioning

confidence: 99%

Different Mechanisms of Drug Resistance in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Messingerová¹,

Imrichova²,

Coculova³

et al. 2016

Myelodysplastic Syndromes

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P-glycoprotein depresses cisplatin sensitivity in L1210 cells by inhibiting cisplatin-induced caspase-3 activation

Cited by 53 publications

References 41 publications

The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin

The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin

Inhibition of Glucosylceramide Synthase Sensitizes Head and Neck Cancer to Cisplatin

Different Mechanisms of Drug Resistance in Myelodysplastic Syndromes and Acute Myeloid Leukemia

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