The resistant cells exhibited enhanced proliferative, clonogenic capacity with significant up-regulation of P-glycoprotein (ABCB1), c-Myc, survivin, β-catenin and a putative cancer-stem-like signature with increased expression of CD44, whereas the loss of E-cadherin signifies induced EMT phenotype.
The effect of synthesized compounds 8a-v was studied against human cancer cell lines for their antiproliferative activity and reversal of multidrug resistance on human MDR1-gene transfected mouse lymphoma cells.
Functional assays further revealed that K176R mutant of CAV1 in cancer cells increased the transport activity of P-glycoprotein and decreased the killing ability of anti-cancer drugs in non-small-cell lung cancer cell lines.
Importantly, the results demonstrated that increased GCS expression in NSCLC cancer specimens correlated with increased expression of P-gp and LRP, molecules known to stimulate cancer cell MDR (r = 0.612 and 0.503, P = 0.01 and 0.035, respectively).
Increased expression of the mdr-1 gene encoding the drug efflux pump P-glycoprotein is a well-established mediator of acquired drug resistance in vitro, and a similar role has been hypothesized in vivo in human malignancy.
Each of three 3435TT, C1236TT, 2677TT genotypes of ABCB1 and their combination was associated with about 50% higher anti-emetic response to 5-HT3 receptor antagonists in the acute phase of chemotherapy in patients with cancer receiving moderately or highly emetogenic chemotherapy.
Finally, whereas evidence of in vitro targeting is not necessarily evidence of in vivo targeting, our results do suggest that radiolabeled antisense DNA against the mdr1 mRNA may potentially be useful for antisense imaging of MDR in cancer.
This provided initial evidence that Pgp may be useful as a gene expression marker for predicting potential responses to doxorubicin/Pluronic formulation in chemotherapy of cancer.
Multidrug resistance (MDR) is a major obstacle in cancer treatment due to the ability of tumor cells to efflux chemotherapeutics via drug transporters (<i>e.g.</i> P-glycoprotein (Pgp; ABCB1)).
P-glycoprotein (P-gp, ABCB1) over-expression, causing a multi-drug resistant (MDR) phenotype, is a major problem in cancer chemotherapy that urgently requires novel approaches.
This study was performed to determine if clinically relevant antimicrobial drugs (i.e., drugs that are used to treat bacterial infections in cancer patients) other than antineoplastic agents can induce expression of P-gp in MCF-7 breast carcinoma cells.
This safety-modified vector should be useful for introducing the MDR1 gene into bone marrow cells to protect normal cells from the toxic effects of cancer chemotherapy.
To clarify the role of MDR1 in this malignancy, we examined the relationship between MDR1 expression and patient outcome in subsets of 60 primary untreated neuroblastomas for which MYCN gene copy number and expression of the multidrug resistance-associated-protein (MRP) gene had been previously characterised.
We found that CpG islands at GSTP1, APC, RASSF1a, PTGS2, and MDR1 were hypermethylated in >85% of prostate cancers and cancer cell lines but not in normal prostate cells and tissues; CpG islands at EDNRB, ESR1, CDKN2a, and hMLH1 exhibited low to moderate rates of hypermethylation in prostate cancer tissues and cancer cell lines but were entirely unmethylated in normal tissues; and CpG islands at DAPK1, TIMP3, MGMT, CDKN2b, p14/ARF, and CDH1 were not abnormally hypermethylated in prostate cancers.
Interest in chloride channels related to cancer first arose when the multidrug resistance protein (MDR/P-glycoprotein) was linked to volume-activated chloride channel activity in cancer cells from patients undergoing chemotherapy.
These findings suggest a novel pathway leading to cancer MDR, in which Snail induces EMT concomitantly with a decrease in GRB2-mediated caveolin-1 phosphorylation, resulting in activation of P-gp.