Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 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

Challenges in the discovery of more potent agents to treat the castration-resistant prostate carcinoma (CRPC) reflect the frustrating condition due to development of its drug-resistance in addition to hormone-refractoriness. Although among the different CRPC therapy modalities, the chemotherapy regimens might seem conceptually outclassed as exhibiting a scant tumor cell-selectivity if compared with new molecular mechanism-based agents (so-called "smart drugs"), nevertheless, combo-therapies which combine the chemotherapeutic highly killing potential with specific mechanism-targeting products, seem to be effective antitumor measures. Thus, both microtubule (taxanes, epothilones, noscapine, Vinca-derivatives) and actin filament (pertenotoxins, cytochalasin D)-targeting agents may supply valuable outcomes in CRPC, either alone or in combination with "smart drugs" such as tyrosine- or multi-kinase receptor blockers, mTOR (mammalian target of rapamicin) inhibitors, monoclonal antibodies against various growth factor signaling receptors. Among the microtubule-inhibiting drugs, taxanes are able, by binding the tubulin, to cause polymerization and stabilization of the microtubules with following suppression of their dynamic properties at the mitotic spindle, that results in cancer cell cycle block at G2/M phase together with apoptosis. Cabazitaxel, a novel taxane-based agent, unlike other taxane compounds, exhibits low propensity for P-glycoprotein (Pgp)-mediated plasmalemmal drug efflux pump, thus, avoiding the development of taxane-resistance. Epothylones are a family of novel microtubule-targeting drugs, like taxane inhibiting microtubule dynamic behaviour at mitotic spindle and, therefore, preventing cancer cells from mitosis. Unlike docetaxel and paclitaxel, epothilones maintain their cytotoxic performance even in cancer overexpressing Pgp. Epothilone B-promoted radiosensitivity enhancement has been shown in radioresistant human prostate cancer cells, because such agent is able to delay DNA- strand break repair together with prolonging cell cycle block. To insightfully understand either microtubule or actin filament meshwork-targeting drug pharmacodynamics, functional cytoskeletal features such as cytoskeleton-related molecule cargo logistics, are preliminary taken into consideration.
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PMID:Taxane- and epothilone-based chemotherapy: from molecule cargo cytoskeletal logistics to management of castration-resistant prostate carcinoma. 2383 35

The use of anticancer drugs is beneficial for patients with malignancies but is frequently associated with the occurrence of electrolyte disorders, which can be hazardous and in many cases fatal. The review presents the electrolyte abnormalities that can occur with the use of anticancer drugs and provides the related mechanisms. Platinum-containing anticancer drugs induce hypomagnesemia, hypokalemia and hypocalcemia. Moreover, platinum-containing drugs are associated with hyponatremia, especially when combined with large volumes of hypotonic fluids aiming to prevent nephrotoxicity. Alkylating agents have been linked with the occurrence of hyponatremia [due to syndrome of inappropriate antidiuretic hormone secretion (SIADH)] and Fanconi's syndrome (hypophosphatemia, aminoaciduria, hypouricemia and/or glucosuria). Vinca alkaloids are associated with hyponatremia due to SIADH. Epidermal growth factor receptor monoclonal antibody inhibitors induce hypomagnesemia, hypokalemia and hypocalcemia. Other, monoclonal antibodies, such as cixutumumab, cause hyponatremia due to SIADH. Tyrosine kinase inhibitors are linked to hyponatremia and hypophosphatemia. Mammalian target of rapamycin inhibitors induce hyponatremia (due to aldosterone resistance), hypokalemia and hypophosphatemia. Other drugs such as immunomodulators or methotrexate have been also associated with hyponatremia. The administration of estrogens at high doses, streptozocin, azacitidine and suramin may induce hypophosphatemia. Finally, the drug-related tumor lysis syndrome is associated with hyperphosphatemia, hyperkalemia and hypocalcemia. The prevention of electrolyte derangements may lead to reduction of adverse events during the administration of anticancer drugs.
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PMID:Electrolyte disorders associated with the use of anticancer drugs. 2693 82

The use of antineoplastic drugs has a central role in treatment of patients affected by cancer but is often associated with numerous electrolyte derangements which, in many cases, could represent life-threatening conditions. In fact, while several anti-cancer agents can interfere with kidney function leading to acute kidney injury, proteinuria, and hypertension, in many cases alterations of electrolyte tubular handling and water balance occur. This review summarizes the mechanisms underlying the disturbances of sodium, potassium, magnesium, calcium, and phosphate metabolism during anti-cancer treatment. Platinum compounds are associated with sodium, potassium, and magnesium derangements while alkylating agents and Vinca alkaloids with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH). Novel anti-neoplastic agents, such as targeted therapies (monoclonal antibodies, tyrosine kinase inhibitors, immunomodulators, mammalian target of rapamycin), can induce SIADH-related hyponatremia and, less frequently, urinary sodium loss. The blockade of epidermal growth factor receptor (EGFR) by anti-EGFR antibodies can result in clinically significant magnesium and potassium losses. Finally, the tumor lysis syndrome is associated with hyperphosphatemia, hypocalcemia and hyperkalemia, all of which represent serious complications of chemotherapy. Thus, clinicians should be aware of these side effects of antineoplastic drugs, in order to set out preventive measures and start appropriate treatments.
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PMID:Electrolyte Disorders Induced by Antineoplastic Drugs. 3250 80