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

Messingerová, Lucia; Imrichova, Denisa; Coculova, Martina; MarianZelina,; Pavlíková, Lucia; Kavcová, Helena; Šereš, Mário; VieraBohacova,; Lakatoš, Boris; Sulová, Zdena; Breier, Albert

doi:10.5772/63483

Cited by 6 publications

(9 citation statements)

References 84 publications

(111 reference statements)

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“…Multidrug resistance represents a major obstacle in the effective treatment of neoplastic diseases including blood malignancies [ 5 ]. Until now, the diverse but well understood mechanisms of MDR have been identified [ 4 ], from which the efflux activity of overexpressed P-gp represents the most frequently occurring molecular cause [ 6 , 7 ]. Therefore, searching for substances that are effective also in cells with overexpressed P-gp represents an important assignment for medicinal chemistry.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, even if the impressive responses of these therapies were fulfilled, several individuals are non-responders and show signs of drug resistance that may occur due to the phenotypic plasticity of cancer cells [ 3 ]. Neoplastic cells use several mechanisms to escape from the cell death effects of anticancer drugs [ 4 ]. Malignant cells could develop resistance to a wide group of structurally unrelated substances with different mechanisms of anticancer action—multidrug resistance (MDR) [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Triorganotin Derivatives Induce Cell Death Effects on L1210 Leukemia Cells at Submicromolar Concentrations Independently of P-glycoprotein Expression

et al. 2018

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The acceleration of drug efflux activity realized by plasma membrane transporters in neoplastic cells, particularly by P-glycoprotein (P-gp, ABCB1 member of the ABC transporter family), represents a frequently observed molecular cause of multidrug resistance (MDR). This multiple resistance represents a real obstacle in the effective chemotherapy of neoplastic diseases. Therefore, identifying cytotoxic substances that are also effective in P-gp overexpressing cells may be useful for the rational design of substances for the treatment of malignancies with developed MDR. Here, we showed that triorganotin derivatives—tributyltin-chloride (TBT-Cl), tributyltin-bromide (TBT-Br), tributyltin-iodide (TBT-I) and tributyltin-isothiocyanate (TBT-NCS) or triphenyltin-chloride (TPT-Cl) and triphenyltin-isothiocyanate (TPT-NCS)—could induce the death of L1210 mice leukemia cells at a submicromolar concentration independently of P-gp overexpression. The median lethal concentration obtained for triorganotin derivatives did not exceed 0.5 µM in the induction of cell death of either P-gp negative or P-gp positive L1210 cells. Apoptosis related to regulatory pathway of Bcl-2 family proteins seems to be the predominant mode of cell death in either P-gp negative or P-gp positive L1210 cells. TBT-Cl and TBT-Br were more efficient with L1210 cells overexpressing P-gp than with their counterpart P-gp negative cells. In contrast, TBT-I and TPT-NCS induced a more pronounced cell death effect on P-gp negative cells than on P-gp positive cells. Triorganotin derivatives did not affect P-gp efflux in native cells measured by calcein retention within the cells. Taken together, we assumed that triorganotin derivatives represent substances suitable for suppressing the viability of P-gp positive malignant cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Triorganotin Derivatives Induce Cell Death Effects on L1210 Leukemia Cells at Submicromolar Concentrations Independently of P-glycoprotein Expression

et al. 2018

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“…The mechanism of AZA and DAC action has not been fully elucidated. In addition to direct effects as cytosine derivatives incorporated into DNA when demethylation is induced, these substances may alter the immunological response to the presence of neoplastically transformed cells or induce several cytotoxic effects, including disruption of nucleic acid and protein metabolism, which leads to apoptosis [ 8 , 9 , 10 ]. These responses make HMA therapy response prediction difficult, and until now, specific molecular assays for distinguishing responders from nonresponders were unavailable [ 6 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Changes in Apoptotic Pathways in MOLM-13 Cell Lines after Induction of Resistance to Hypomethylating Agents

Janotka

Messingerová

Šimoničová

et al. 2021

IJMS

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We established the following two variants of the MOLM-13 human acute myeloid leukemia (AML) cell line: (i) MOLM-13/DAC cells are resistant to 5-aza-2′-deoxycytidine (DAC), and (ii) MOLM-13/AZA are resistant to 5-azacytidine (AZA). Both cell variants were obtained through a six-month selection/adaptation procedure with a stepwise increase in the concentration of either DAC or AZA. MOLM-13/DAC cells are resistant to DAC, and MOLM-13/AZA cells are resistant to AZA (approximately 50-fold and 20-fold, respectively), but cross-resistance of MOLM-13/DAC to AZA and of MOLM-13/AZA to DAC was not detected. By measuring the cell retention of fluorescein-linked annexin V and propidium iodide, we showed an apoptotic mode of death for MOLM-13 cells after treatment with either DAC or AZA, for MOLM-13/DAC cells after treatment with AZA, and for MOLM-13/AZA cells after treatment with DAC. When cells progressed to apoptosis, via JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide) assay, we detected a reduction in the mitochondrial membrane potential. Furthermore, we characterized promoter methylation levels for some genes encoding proteins regulating apoptosis and the relation of this methylation to the expression of the respective genes. In addition, we focused on determining the expression levels and activity of intrinsic and extrinsic apoptosis pathway proteins.

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“…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: 99%

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

Cited by 6 publications

References 84 publications

Triorganotin Derivatives Induce Cell Death Effects on L1210 Leukemia Cells at Submicromolar Concentrations Independently of P-glycoprotein Expression

Triorganotin Derivatives Induce Cell Death Effects on L1210 Leukemia Cells at Submicromolar Concentrations Independently of P-glycoprotein Expression

Changes in Apoptotic Pathways in MOLM-13 Cell Lines after Induction of Resistance to Hypomethylating Agents

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

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