Resistance to chemotherapy occurs in cancer cells because of intrinsic or acquired changes in expression of specific proteins. We have studied resistance to natural product chemotherapeutic agents such as doxorubicin, Vinca alkaloids, and taxol, and to the synthetic drug cisplatin. In both cases, cells become simultaneously resistant to multiple drugs because of reductions in intracellular drug concentrations. For the natural product drugs, this cross-resistance is frequently due to expression of an energy-dependent drug efflux system (ABC transporter) known as P-glycoprotein (P gp), the product of the MDR1 or ABCB1 gene, or to other members of the ABC transporter family. To explore the possibility that other members of the ABC family of transporters may be involved in drug resistance in cancer, we have developed real-time PCR for detection of most of the 48 known ABC transporters; these techniques have been used to correlate expression of novel ABC transporters in cancer cell lines of known drug resistance. Expression of approximately 30 ABC transporters has been shown to correlate with resistance to specific cytotoxic drugs. Transfection of several of these transporters has confirmed that they confer resistance to the drugs detected in the correlation studies. Furthermore, this analysis has revealed that some drugs are more toxic to P-gp expressing cells than to non-expressors, suggesting a novel approach to treatment of MDR cancers. Several different chemical classes with this property, including thiosemicarbazides, have been identified. One compound, NSC73306, has been studied in detail and shown to kill P-gp-expressing cells with high specificity by blocking them in S phase. Surviving cells do not express P-gp and are sensitive to chemotherapy with natural product drugs such as anthracyclines, paclitaxel and Vinca alkaloids. A quantitative structure activity analysis of NSC73306 analogs has yielded several additional compounds with a similar ability to kill P-gp-expression cells, but improved solubility properties. Studies on the normal function of P-gp suggest that it is involved in normal uptake and distribution of many drugs. Common polymorphic variants of P-gp have been detected, but coding polymorphisms do not appear to alter the drug transport functions of P-gp. However, a synonymous polymorphism (C3435T, no amino acid change) in the setting of a specific P-gp haplotype can affect efficiency of P-gp pumping by altering the rhythm of protein folding and changing substrate and inhibitor interactions with P-gp. Use of the MDR1 gene as a dominant selectable marker in gene therapy has focused on the development of SV40 as a vector for delivery of MDR1. Using recombinant SV40 capsid proteins, it is possible to package DNA and RNA in vitro. In particular, siRNA can be delivered with high efficiency and at much lower concentrations than are needed for lipofection. Delivery of toxic DNAs, such as Pseudomonas exotoxin cDNA, can be used to target cancers in vitro and in mouse xenoplant models. The ultimate level of drug accumulation in a cell depends on both the rate of drug uptake as well as the rate of efflux. We have begun to explore the role of known solute carrier (SLC and SLCO) transporters as contributors to patterns of drug sensitivity and resistance in cancer cells. Our initial approach has been to correlate expression of SLC and SLCO transporters with degree of drug sensitivity in the NCI-60 cell lines. Several hits were obtained, indicating that expression of uptake transporters is associated with drug sensitivity.
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| Kannan, Pavitra; Brimacombe, Kyle R; Kreisl, William C et al. (2011) Lysosomal trapping of a radiolabeled substrate of P-glycoprotein as a mechanism for signal amplification in PET. Proc Natl Acad Sci U S A 108:2593-8 |
| Shomron, Noam; Hamasaki-Katagiri, Nobuko; Hunt, Ryan et al. (2010) A splice variant of ADAMTS13 is expressed in human hepatic stellate cells and cancerous tissues. Thromb Haemost 104:531-5 |
| Kannan, Pavitra; Brimacombe, Kyle R; Zoghbi, Sami S et al. (2010) N-desmethyl-loperamide is selective for P-glycoprotein among three ATP-binding cassette transporters at the blood-brain barrier. Drug Metab Dispos 38:917-22 |
| Gillet, Jean-Pierre; Macadangdang, Benjamin; Fathke, Robert L et al. (2009) The development of gene therapy: from monogenic recessive disorders to complex diseases such as cancer. Methods Mol Biol 542:5-54 |
| Paterson, Jill K; Gottesman, Michael M (2007) P-Glycoprotein is not present in mitochondrial membranes. Exp Cell Res 313:3100-5 |
| Kimchi-Sarfaty, Chava; Marple, Andrew H; Shinar, Shiri et al. (2007) Ethnicity-related polymorphisms and haplotypes in the human ABCB1 gene. Pharmacogenomics 8:29-39 |
| Sauna, Zuben E; Kimchi-Sarfaty, Chava; Ambudkar, Suresh V et al. (2007) The sounds of silence: synonymous mutations affect function. Pharmacogenomics 8:527-32 |
| Gottesman, Michael M; Ling, Victor (2006) The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett 580:998-1009 |
| Szakacs, Gergely; Paterson, Jill K; Ludwig, Joseph A et al. (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219-34 |
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