Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Verapamil, Ca++ channel antagonist, has proven clinically useful in the reversal of multiple drug resistance, which is a major detriment to chemotherapy. Recently, verapamil alone has been shown to diminish proliferation in a variety of neoplastic cell lines. Using the patch-clamp technique, the action of verapamil on voltage-gated K+ channels in two cell lines of human small-cell carcinoma of the lung, NCI-H146 and NCI-H82, was investigated. With inward Na+ current suppressed, virtually all control cells exhibited a slowly inactivating outward current that was insensitive to alterations in the external Ca++ concentration. Externally applied verapamil enhanced the rate and extent of outward K+ current (IK) inactivation. Verapamil at a concentration of 20 microM diminished peak IK, evoked by a test pulse to +60 mV from a holding potential of -80 mV, from 1.38 +/- 0.11 nA (mean +/- S.E.M., n = 29 cells) to 0.56 +/- 0.13 nA (n = 11) and caused IK to decay to less than 20% of the peak current within 60 msec. After blocking IK and Na+ current, Ca++ current (ICa) was measured in the presence of 10 mM Ca++. The addition of 100 microM verapamil to the external bath resulted in a 53% reduction of H146 ICa. Peak ICa fell from 81 +/- 9 pA (n = 22) to 38 +/- 8 pA (n = 12). Examination of the whole-cell K+ current on single cells before and immediately after the addition of 100 microM verapamil clearly revealed that the drug had no effect on the initial activation phase of IK, suggesting that K+ channels first open before interacting with the drug.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Verapamil-induced blockade of voltage-activated K+ current in small-cell lung cancer cells. 185 Apr 64

Human lung carcinoma A549-T27 cells were used to determine the effect of diamide on cadmium accumulation. Treatment of the cells with diamide decreased their cellular glutathione content to 51.6 +/- 7% of control and significantly decreased their cadmium accumulation both as a function of time and as a function of Cd2+ concentration. Verapamil also decreased cadmium accumulation. Its effect compares well in magnitude with that which resulted from diamide treatment. No additive effect was observed when the cells were simultaneously treated with diamide and verapamil. The results suggest that a change in the GSH/GSSG ratio affects cadmium uptake. Further, calcium channels may be involved in cadmium uptake by A549-T27 cells in a fashion that is dependent on sulfhydryl status.
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PMID:Diamide reduces cadmium accumulation by human lung carcinoma A549 cells. 216 Jul 46

The treatment of cancer is often impeded by the emergence of drug-resistant clones. Drug resistance is in many cases due to a decreased drug accumulation in the tumor cell. Membrane-acting agents, by increasing cell permeability, might counteract the loss of sensitivity to drugs. In the present study, the effect of two membrane-acting agents, hyperthermia and the calcium channel blocker verapamil, on the action of adriamycin (ADR) on Lewis lung carcinoma (3LL) was examined. Hyperthermia increased drastically the antitumoral effect of ADR. The effectiveness of the combined ADR-hyperthermia treatment was proportional to the ADR dose and to the degree of hyperthermia. Verapamil had a similar effect but at higher ADR doses. Treatment modalities designed for the circumvention of drug resistance could be one approach in the attempt to find a way to control cancer.
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PMID:Combined effect in vitro of chemotherapy with agents acting on the cell membrane of Lewis lung carcinoma. 233 31

The effect of the combined administration of verapamil (i.p. twice daily) and doxorubicin (i.v. once weekly) was tested in mice bearing the following: (a) a tumor with induced resistance to doxorubicin (B16VDXR melanoma line); (b) a tumor inherently resistant (MXT mammary carcinoma); and (c) four solid tumors sensitive to doxorubicin (B16 melanoma, B16V melanoma line, M5076 reticulum cell sarcoma, and Lewis lung carcinoma). Verapamil, given according to this treatment schedule, reached peak plasma concentrations of 3 microM. Such treatment did not enhance doxorubicin activity on either inherently or induced resistant tumors, whereas it significantly enhanced doxorubicin growth inhibition in all the sensitive tumors except the Lewis lung carcinoma. Doxorubicin pharmacokinetics after administration of the drug alone and in combination with verapamil was analyzed after the first and repeated treatments in animals bearing B16 melanoma or its resistant subline B16VDXR. The resistance of the B16VDXR line was associated with the ability of the tumor to retain less doxorubicin (AUC = 83 micrograms h/g) than the sensitive tumor B16 (AUC = 204 micrograms h/g) in spite of similar initial levels. The potentiating effect of doxorubicin activity by verapamil in B16 melanoma was not associated with increased doxorubicin levels or retention in the tumor, nor were differences in doxorubicin levels or retention found in the B16VDXR line. The combined treatment did not modify doxorubicin pharmacokinetics in plasma, heart, or spleen. These studies suggest that verapamil in vivo is ineffective in potentiating doxorubicin activity in tumors against which doxorubicin is inactive, that sensitive tumors are heterogeneous in their sensitivity to modulation by verapamil, and that this effect is not associated with modification of doxorubicin pharmacokinetics.
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PMID:Effect of verapamil on doxorubicin activity and pharmacokinetics in mice bearing resistant and sensitive solid tumors. 337 Jul 42

Cultured cell lines LL, B16, C26, and C38 established from mouse solid tumors of Lewis lung carcinoma, B16 melanoma, and colon adenocarcinomas 26 and 38, respectively, showed inherently different resistance to vincristine (VCR) in vitro. The inherent resistance to VCR of these cell lines was related to the ability of the cells to accumulate VCR. Verapamil, a calcium antagonist with coronary vasodilator activity, enhanced the cytotoxicity of VCR against these cell lines depending upon their susceptibility to VCR. C26 cells, the most resistant, became the most susceptible to VCR with a nontoxic dose of verapamil. A 12-fold increase in VCR cytotoxicity occurred. Only a 2.5-fold increase in VCR cytotoxicity was observed for B16 cells, the most sensitive cells. VCR cytotoxicity against each cell line reached almost the same level by verapamil (2.2 to 6.6 microM). Thus, the inherent resistance to VCR among the tumor lines was circumvented. Verapamil enhanced the cellular accumulation of VCR. A 3- to 4-fold increase in cellular VCR occurred in C26 cells, while approximately a 2-fold increase was observed for B16 and LL cells. A similar rate of enhancement was observed for both bound and free VCR, indicating that verapamil does not enhance the affinity of VCR to tubulin. Verapamil inhibited the outward transport of VCR from the cells. The most prominent inhibition was observed for C26 cells. Circumvention of inherent resistance of tumor cells to VCR by verapamil could be attained through an enhanced cellular accumulation of VCR in each of the tumor cells. The enhancement of VCR cytotoxicity and circumvention of inherent VCR resistance by verapamil could be explained by the cellular concentration of VCR, and also it might be related to the extent of VCR binding to tubulin in the cell. The chemotherapeutic effect of VCR is significantly enhanced by verapamil in colon adenocarcinoma 26-bearing mice.
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PMID:Promotion by verapamil of vincristine responsiveness in tumor cell lines inherently resistant to the drug. 684 94

Based on our initial results on the effects of several ATP-binding cassette (ABC) transporter inhibitors on rhodamine-123 efflux from A549, a human lung carcinoma, and MES-SA, a human uterine sarcoma cell line, the aim of this study was to identify the transporter responsible for this export. Export of two fluorescent dyes, rhodamine-123 and calcein, was investigated in both cell lines by testing five commonly used inhibitors of ABC transporters: verapamil, cyclosporin A, MK571, GF129018 and fumitremorgin C. A very high degree of correlation (R(2)=0.91-0.99) between results obtained in the two cell lines suggested that the same transporter was involved in the export of tested fluorescent substrates in both cell lines. Expression analysis and gene silencing techniques, as well as transport of additional substrate 5(6)-carboxy-2',7'-dichlorofluorescein (CDCF) on membrane vesicles revealed that the transporter was multidrug resistance related protein 2 (MRP2, ABCC2). Furthermore, it was found that the tested modulators showed very diverse effects on the export of three fluorescent substrates via MRP2, with some modulators being inhibitory in one, while having no effect or even stimulating the transport in the other fluorescent dye assay. Verapamil inhibited rhodamine-123, but stimulated CDCF transport and did not affect calcein export. GF129018 did not affect calcein and CDCF transport, but it inhibited rhodamine-123 transport. These results demonstrate the importance of studying various combinations of potential substrates and modulators of MRP2 in order to estimate possible drug-drug interactions in living organisms. In addition, A549 and MES-SA cells were shown to be good cell models for studying interactions of compounds with human MRP2.
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PMID:Characterization of rhodamine-123, calcein and 5(6)-carboxy-2',7'-dichlorofluorescein (CDCF) export via MRP2 (ABCC2) in MES-SA and A549 cells. 2160 68

Schweinfurthins are intriguing natural products with anti-cancer activities and as yet incompletely understood mechanisms of action. We investigated whether inhibitors of P-glycoprotein (Pgp), in a manner analogous to other natural products, might enhance schweinfurthins' growth inhibitory actions by increasing intracellular schweinfurthin levels. Both the schweinfurthin-sensitive glioblastoma multiforme cell line SF-295 and relatively insensitive lung carcinoma cell line A549 were treated with 2 schweinfurthin analogs: 3-deoxyschweinfurthin B-p-nitro bis-stilbene (3dSB-PNBS) and 5'-methylschweinfurthin G (methyl-G). There was a synergistic enhancement of growth inhibition with the combination of the Pgp inhibitor verapamil and both analogs in SF-295 cells. Methyl-G, verapamil, and the combination did not result in alterations to intracellular calcium concentration. Verapamil increased the intracellular concentration of 3dSB-PNBS in both SF-295 and A549 cells in a Pgp-independent manner. Methyl-G, verapamil, and the combination do not result in increased ER stress. Methyl-G increased the intracellular concentration of a known Pgp substrate, Rhodamine 123 in SF-295 cells. Reduction of cellular cholesterol leads to the accumulation of Pgp substrates, as Pgp requires cholesterol for proper function. Since 3dSB enhances lovastatin-induced upregulation of the cholesterol efflux pump ABCA1, it is intriguing that co-treatment with cholesterol rescued the methyl-G-induced increase in Rhodamine 123 intracellular concentration. These studies support the hypothesis that verapamil potentiates the schweinfurthin growth inhibitory effect by increasing its intracellular concentration.
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PMID:Calcium and P-glycoprotein independent synergism between schweinfurthins and verapamil. 2604 59