Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The multidrug resistance gene 1 (MDR1) product, P-glycoprotein (P-gp), pumps out a variety of anticancer agents from the cell, including anthracyclines, Vinca alkaloids, and taxanes. The expression of P-gp therefore confers resistance to these anticancer agents. In our present study, we found that FTI-277 (a farnesyltransferase inhibitor), U0126 [an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)], and 17-allylamino-17-demethoxygeldanamycin (an inhibitor of heat shock protein 90) reduced the endogenous expression levels of P-gp in the human colorectal cancer cells, HCT-15 and SW620-14. In contrast, inhibitors of phosphatidylinositol 3-OH kinase, mammalian target of rapamycin, p38 mitogen-activated protein kinase, and c-Jun NH(2)-terminal kinase did not affect P-gp expression in these cells. We further found that U0126 down-regulated exogenous P-gp expression in the MDR1-transduced human breast cancer cells, MCF-7/MDR and MDA-MB-231/MDR. However, the MDR1 mRNA levels in these cells were unaffected by this treatment. PD98059 (a MEK inhibitor), ERK small interfering RNA, and p90 ribosomal S6 kinase (RSK) small interfering RNA also suppressed P-gp expression. Conversely, epidermal growth factor and basic fibroblast growth factor enhanced P-gp expression, but the MDR1 mRNA levels were unchanged in epidermal growth factor-stimulated cells. Pulse-chase analysis revealed that U0126 promoted P-gp degradation but did not affect the biosynthesis of this gene product. The pretreatment of cells with U0126 enhanced the paclitaxel-induced cleavage of poly(ADP-ribose) polymerase and paclitaxel sensitivity. Furthermore, U0126-treated cells showed high levels of rhodamine123 uptake. Hence, our present data show that inhibition of the MEK-ERK-RSK pathway down-regulates P-gp expression levels and diminishes the cellular multidrug resistance.
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PMID:Inhibition of the mitogen-activated protein kinase pathway results in the down-regulation of P-glycoprotein. 1762 Apr 38

Farnesol is a non-cyclic sesquiterpene (isoprenoid) found in the essential oils of many plants. In cancer biology, farnesylation of mutated Ras oncoproteins allows the proteins to dock to the membrane and be functionalized. Therefore, farnesyltransferase is a target for drug development to inhibit Ras. Farnesol exhibits cytotoxic activity against tumor cells in vitro and in vivo, implying that novel treatment strategies may be devised independent of Ras farnesylation. Tumors frequently develop resistance towards standard chemotherapies, and thus novel agents are urgently required that bypass the cross-resistance evoked by established anticancer drugs. We investigated whether classical mechanisms of drug resistance such as ATP-binding cassette transporters (P-glycoprotein/MDR1, MRP1, BCRP), the tumor suppressor gene TP53, and the oncogene EGFR play a role in the response of tumor cells to farnesol. Remarkably, none of these genes conferred resistance to farnesol, indicating that this compound may be useful for the treatment of otherwise drug-resistant and refractory tumors expressing these mechanisms of resistance. Furthermore, we applied a pharmacogenomic approach to explore molecular determinants of sensitivity and resistance to farnesol. Among the candidates were genes involved in apoptosis (STAB2, NUMBL), regulation of transcription (CDYL, FOXA2) and diverse other functional groups (INE1, CTRL, MRS2, NEB, LMO7, C9orf3, EHBP1). The fact that these genes are not associated with resistance to traditional anticancer drugs suggests farnesol may possess a novel mechanism of action, and consequently might bypass drug resistance to established chemotherapeutics.
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PMID:Molecular determinants of cancer cell sensitivity and resistance towards the sesquiterpene farnesol. 2392 45