P-glycoprotein overexpression

Laulimalide is also active in P-glycoprotein overexpressing cells [129]. Despite these similarities, laulimalide does not bind the paclitaxel binding site... 

Hoki Y, Fujimori A, Pommier Y. 1997. Differential cytotoxicity of clinically important camptothecin derivatives in P-glycoprotein-overexpressing cell lines. Cancer Chemother. Pharmacol. 40 433— 38... 

Broxterman, H.J., Pinedo, H.M., Kuiper, C.M., Schuurhuis, G.J. and Lankelma, J. (1989) Glycolysis in P-glycoprotein-overexpressing human tumor cell lines. Effects of resistance-modifying agents. FEBS Letters, 247, 405-410. 

Raviv, Y., A. Puri and R. Blumenthal. P-glycoprotein-overexpressing multidrug-resistant cells are resistant to infection by enveloped viruses that enter via the plasma membrane. FASEB J. 14 511-515, 2000. 

It was found that RNAMM overexpression by transfection into normal fibroblasts turns them into metastatic fibrosarcoma cells. The ability of hyaluronan to inhibit cancer cell growth is not related to mutations of r53/r21 or Rb-, deletion of pl6, Fas-stability, absence of caspase-3 or P-glycoprotein overexpression. 

The use of Caco-2 cell monolayers has gained in popularity as an in vivo human absorption surrogate moreover, the monolayers are generally accepted as a primary absorption screening tool by several pharmaceutical companies [10]. However, Caco-2 cell permeability measurements exhibit certain limitations due to the mechanisms involved. Both passive and active pathways exist active transport tends to increase the absorption across the cells and, since Caco-2 cells overexpress the P-glycoprotein (P-gp) efflux pump, the absorption of some compounds across these cells may be underestimated. 

Multidrug resistance (MDR) is the name ascribed to the phenomenon whereby cancer cells and tumors develop resistance to chemotherapeutic agents. Conceptually, this can be viewed as a survival response whereby cancer cells endeavor to ward off cytotoxic compounds. Mechanistically, MDR is typically mediated by overexpression of P-glycoprotein (P-gp aka ABCB1) or other plasma membrane ATPases that export cytotoxic drugs used in chemotherapy, thereby reducing their efficacy. 

Cancer cells typically overexpress ATP-dependent transmembrane transporters capable of expelling a wide variety of chemically unrelated drugs used in cancer therapy. This phenomenon is known as multidrug resistance (MDR). Inhibition of MDR proteins, such as the P-glycoprotein (Pgp), to prevent drug efflux during cancer therapy has thus potential clinical value. 

Although not a taxane, ixabepilone is a novel microtubule inhibitor that was recently approved for metastatic breast cancer in combination with the oral fluoropyrimidine capecitabine or as monotherapy. It is a semisynthetic analog of epothilone B, and is active in the M phase of the cell cycle. This agent binds directly to 6-tubulin subunits on microtubules, leading to inhibition of normal microtubule dynamics. Of note, this agent continues to have activity in drug-resistant tumors that overexpress P-glycoprotein or tubulin mutations. The main adverse effects include myelosuppression, hypersensitivity reactions, and neurotoxicity in the form of peripheral sensory neuropathy. 

M., et al. (2000) P(0) glycoprotein overexpression causes congenital hypomyelination of peripheral nerves. J Cell Biol 148, 1021-1034. 

Hsu SI, Lothstein L, Horwitz SB. Differential overexpression of three mdr gene family members in multidrug-resistant J774.2 mouse cells. Evidence that distinct P-glycoprotein precursors are encoded by unique mdr genes. J Biol Chem 1989 264 (20) 12053-12062. 

Lentz KA, Polli JW, Wring SA, Humphreys JE, Polli JE (2000) Influence of passive permeability on apparent P-glycoprotein kinetics. Pharm Res 17 1456-1460 Litman T, Brangi M, Hudson E et al. (2000) The multidrug resistance phenotype associated with overexpression of the new ABC half-transporter MXR (ABCG2). J Cell Sci 113 2011-2021... 

---