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At least 307 records · Page 17Linked to original sources
PubMed1989

Human multidrug resistant KB cells overexpress protein kinase C: involvement in drug resistance.

Among the many phenotypic characteristics of multidrug resistance (MDR), the presence of P-glycoprotein is nearly always observed, and it appears that the plasma membrane of the multidrug resistant cell is integrally involved in controlling drug resistance. Another membrane-associated protein kinase, protein kinase C (PKC), has been shown to regulate the flow of information to the cell interior and to control the efflux of a number of different compounds. We therefore initiated a study of PKC and MDR. We found that multidrug resistant sublines from both mouse sarcoma 180 and human KB lines exhibited 80-90% increases in basal PKC activity. The mechanism of the increase appears to be quite different in the two cell lines. The human KB cells overexpress the alpha isozyme of PKC, commensurate with the increase in alpha-PKC protein, whereas the mouse cells do not overexpress alpha-mRNA but increase alpha-PKC protein. Furthermore, it appears that PKC activity plays a functional role in drug resistance, since inhibition of endogenous PKC activity by staurosporine resulted in decreased resistance to Adriamycin. We also found that phosphorylation of MDR cell membrane vesicles by purified PKC, followed by immunoprecipitation of P-glycoprotein with monoclonal antibody C219, resulted in a level of phosphorylation of P-glycoprotein that was greater than the endogenous phosphorylation level. The data presented indicate that MDR cells of diverse species exhibited enhanced PKC activity but that the mechanisms were different. The increased kinase activity may have biological relevance to MDR since PKC appears to be coupled to P-glycoprotein function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1975

Partial purification and properties of an endoribonuclease isolated from human KB cells.

With the use of a precursor to Escherichia coli tRNA-Tyr as a substrate, we have detected and partially purified a novel endoribonuclease from the cytoplasm of human KB tissue culture cells. This activity, which we have called RNase NU, cleaves the tRNA precursor at two sites in that part of the molecule which is not included in the mature tRNA sequence and which is normally degraded in vivo. In keeping with this observation, we have found that, of a variety of substrates tested, only those which are unstable in vivo are attacked by RNase NU. RNase NU can be purified from the 0.2 M NH4Cl wash of ribosomes followed by ammonium sulfate fractionation and DEAE-Sephadex chromatography. RNase NU cleaves RNA to create 3'-phosphate-terminated oligonucleotides. It has a pH optimum near 8.0, requires either a monovalent cation (NH4+ is most efficient) or Ca-2+ for optimal activity, and is inhibited by 0.1 M PO4-3-. In the course of purifying RNase NU we have detected and studied the intracellular distribution of other ribonuclease activities in human KB cells.

Base Sequence↗
PubMedDate not supplied

Inhibitory effects of a novel marine terpenoid on sensitive and multidrug resistant KB cell lines.

Mechanisms of growth inhibition by the novel marine compound dehydrothyrsiferol (DHT) were investigated in a sensitive and an MDR+ human epidermoid cancer cell line. DHT was found to circumvent multidrug resistance mediated by P-glycoprotein. Cell cycle analysis revealed an accumulation in S-phase. The anchorage independent clonogenic growth in soft agar was not significantly reduced at IC50 concentrations. Reduced cell growth caused by induction of apoptotic or necrotic cell death could not be verified. Therefore, cell proliferation during an incubation period of five days was measured and found to be significantly reduced. We conclude that growth inhibition by dehydrothyrsiferol in KB cancer cells is not mediated by apoptosis but by growth retardation; the reasons for this are worth being investigated in detail.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Reversal of multidrug resistance in KB cells with tea polyphenol antioxidant capacity.

Tea polyphenol (TP), (-)-epigallocatechin gallate (EGCG) in particular, were examined for their reversal effects on multidrug resistance (MDR) with their antioxidant capacities. TP and EGCG were proved to exert reversal effects on drug resistance KB-A-1 cells by 5.2 and 2.5 times, respectively, but no such effects were found on drug sensitive KB-3-1 cells. With a redox indicator 6-carboxy-2',7'-dichlorodihydrofluorescein (CDCFH), it could be found that the intracellular reactive oxygen species (ROS) decreased in the KB-3-1 cells, which was induced by different concentrations of doxorubicin, whereas the intracellular ROS induced by doxorubicin in KB-A-1 cells maintained a high level. Such observation suggests that drug resistant cells undergo oxidative stress. Furthermore, this elevated redox level in KB-A-1 cells was inhibited by either TP or EGCG. These results demonstrate that the reversal effect of TP and EGCG on MDR acts, at least in part, regulating the doxorubicin induced intracellular concentration of ROS.

Antioxidants↗
PubMed1991

Interaction of organic chemicals with P-glycoprotein in the adrenal gland, kidney, and a multidrug-resistant KB cell.

P-glycoprotein (P-gp) is thought to mediate the transport of anti-cancer drugs and to be responsible for the multidrug-resistant (MDR) phenotype in tumor cells. However, the function of P-gp in normal tissues is still not well understood. We present evidence indicating that the active efflux of several structurally unrelated organic compounds is mediated by P-gp in multidrug-resistant KB (KB-C2) cells and that these compounds interact with P-gp in the kidney and adrenal gland. The photoactive radioactive calcium channel blocker [3H]azidopine labels a protein of approximately 140 kDa in crude membrane fractions from human kidney and adrenal gland and a 130-kDa protein from bovine adrenal gland. These photolabeled proteins are immunoprecipitated with an anti-P-gp antibody. Photolabeling is inhibited by vinblastine, reserpine, and several other organic chemicals. These data indicate that the kidney and adrenal gland express P-gp (or a protein closely related to P-gp) that can interact with several organic compounds and that the P-gp expressed in these tissues has a drug-binding site similar to that of P-gp in KB-C2 cells. Our findings thus strongly support the hypothesis that P-gp can transport a wide variety of organic chemicals as well as anti-cancer drugs and that one of the physiological functions of P-gp is the excretion of certain classes of organic compounds.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Reversal of P-glycoprotein and multidrug-resistance protein-mediated drug resistance in KB cells by 5-O-benzoylated taxinine K.

A newly synthesized taxoid originally from the Japanese yew Taxus cuspidata, 5-O-benzoylated taxinine K (BTK) was examined for its ability to reverse P-glycoprotein (P-gp) and multidrug resistance protein (MRP)-mediated multidrug resistance. BTK reversed the resistance to paclitaxel, doxorubicin (ADM), and vincristine (VCR) of KB-8-5 and KB-C2 cells that overexpress P-gp by directly interacting with P-gp. BTK also moderately reversed the resistance to ADM of KB/MRP cells that overexpress MRP. However, BTK neither inhibited the transporting activity of MRP nor reduced intracellular glutathione levels in KB/MRP cells. BTK shifted the distribution of ADM in KB/MRP cells from punctate cytoplasmic compartments to the nucleoplasm and cytoplasm by inhibiting acidification of cytoplasmic organelles. These two functions of BTK make it able to reverse both P-gp- and MRP-mediated MDR. BTK in combination with ADM should be useful for treating patients with tumors that overexpress both P-gp and MRP.

ATP Binding Cassette Transporter, Subfamily B↗