Changes in gene expression profile in two multidrug resistant cell lines derived from a same drug sensitive cell line

Moreira, Miguel Ângelo Martins; Bagni, Carolina; Pinho, Marcos Barcelos de; Mac-Cormick, Thaís Messias; Mota, Mateus dos Santos; Pinto-Silva, Flávio Eduardo; Daflon-Yunes, Nathalia; Rumjanek, Vivian M.

doi:10.1016/j.leukres.2014.06.001

Cited by 34 publications

(39 citation statements)

References 39 publications

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“…P-gp mRNA also tracks protein expression in human brains. In several multidrug resistant (MDR) leukemic cell lines increased MDR transcription and P-gp expression are associated with promoter demethylation (Moreira et al 2014). It appears that activation of P-gp protein is preceded by an increase in P-gp mRNA which is also associated with activation of the nuclear factor kappa B (NF-kB) (Zhang et al 2014; Fan et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier

Osgood

Miller

Messier

et al. 2017

Neurobiology of Aging

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Decreased clearance of potentially toxic metabolites, due to aging changes, likely plays a significant role in the accumulation of amyloid-beta peptides (Aβ) and other macromolecules in the brains of the elderly and in Alzheimer’s disease (AD). Aging is the single most important risk factor for AD development. Aβ transport receptor proteins expressed at the blood-brain barrier (BBB) are significantly altered with age: the efflux transporters LRP-1 and P-gp are reduced, whereas the influx transporter RAGE is increased. These receptors play an important role in maintaining brain biochemical homeostasis. We now report that, in a rat model of aging, gene transcription is altered in aging, as measured by Aβ receptor gene mRNA at 3, 6, 9, 12, 15, 20, 30 and 36 months. Gene mRNA expression from isolated cerebral microvessels was measured by qPCR. LRP-1 and P-gp mRNA were significantly reduced in aging, and RAGE was increased, in parallel with the changes seen in receptor protein expression. Transcriptional changes appear to play a role in aging alterations in BBB receptor expression and Aβ accumulation.

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Section: Discussionmentioning

confidence: 99%

Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier

Osgood

Miller

Messier

et al. 2017

Neurobiology of Aging

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“…In this context, ABCB1-mediated efflux activity was demonstrated to be disconnected from the translocation of ceramides on Golgi (48), and the ABCC1 inhibitor MK-571 was shown to affect retrograde membrane transport and to reduce GlcCer formation (49), evidences that point to at least partial involvement of ABCC in regulating sphingolipid levels. Albeit our results concerning ABCC inhibition could not be directly associated to ABCC1 since CFDA, PRB and MK-571 act as substrates and inhibitors to other members from ABCC subfamily (50), to the best of our knowledge, neither Lucena-1 nor FEPS express ABCC2 or express in significantly lower levels than ABCC1 (51). The participation of other ABCC subfamily members such as ABCC3 and ABCC4, however, could not be discarded and should be taken into account in future studies.…”

Section: Discussionmentioning

confidence: 60%

Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differential modulation of ABC transporters on chronic myeloid leukemias

Salustiano

Costa

Freire-de-Lima

et al. 2020

Preprint

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Multidrug resistance (MDR) in cancer manifests due to cross-resistance to chemotherapeutic drugs with neither structural nor functional relationship, markedly by increased expression and activity of ABC superfamily transporters. Evidences indicate sphingolipids as substrates to ABC proteins in processes such as cell signaling, membrane biosynthesis and inflammation, and products of its biosynthetic route were shown to favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key cell regulator enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Under stress, cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after assimilation into GlcCer by UGCG. Given that cancer cells seem to mobilize UGCG and increase GSL contents for the clearance of ceramides ultimately contributing to treatment failure, we studied how inhibiting GSL biosynthesis would affect the MDR phenotype of chronic myeloid leukemias. Results indicate that MDR associates to higher expression of UGCG and to a complex GSL profile. Inhibition of this glucosyltransferase greatly reduced GM1 expression, and cotreatment with standard chemotherapeutics sensitized cells leading to mitochondrial membrane potential loss and apoptosis. Despite reducing ABCB1 expression, only the ABCC-mediated efflux activity was affected. Consistently, efflux of C6-ceramide, one byproduct of UGCG downregulation, was reduced after inhibition of ABCC-mediated transport. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, overcoming drug resistance through distinct mechanisms. This work brings more comprehension about the involvement of GSL for chemotherapy failure, and modulation of its contents emerges as an intervention targeted to MDR leukemias.

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“…Accumulating evidence suggests that aberrant DNA methylation is involved in the drug resistance of tumor cells and influences the prognosis of patients with AML (30,31). AML is complex and has numerous subtypes and differences among individuals, which makes it difficult to predict the therapeutic outcomes of treatments.…”

Section: Discussionmentioning

confidence: 99%

CDKN2B, SLC19A3 and DLEC1 promoter methylation alterations in the bone marrow of patients with acute myeloid leukemia during chemotherapy

Hong

Chen

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Previous studies have demonstrated that promoter hypermethylation of tumor suppressor genes contributes to the occurrence and development of acute myeloid leukemia (AML). However, the association of DNA methylation with chemotherapeutic outcomes remains unknown. In the present study, 15 patients with AML were recruited, and the promoter methylation status of cyclin-dependent kinase inhibitor 2B (CDKN2B), solute carrier family 19 member 3 (SLC19A3) and deleted in lung and esophageal cancer 1 (DLEC1) genes was examined prior to and following various chemotherapeutic regimens in order to identify any alterations. The results suggested that chemotherapy-induced hypermethylation of CDKN2B and DLEC1 may be specific to males and females, respectively, and that there were no alterations in SLC19A3 methylation following chemotherapy. These results may provide an improved understanding of gene methylation to guide the development of an individualized chemotherapy for AML. Due to the complexity of AML and the wide range of treatment types, future studies with a larger sample size are required in order to verify the results of the present investigation.

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Changes in gene expression profile in two multidrug resistant cell lines derived from a same drug sensitive cell line

Cited by 34 publications

References 39 publications

Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier

Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier

Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differential modulation of ABC transporters on chronic myeloid leukemias

CDKN2B, SLC19A3 and DLEC1 promoter methylation alterations in the bone marrow of patients with acute myeloid leukemia during chemotherapy

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