Abstract
P-glycoprotein (Pgp) extrudes a large variety of chemotherapeutic drugs from the cells, causing multidrug resistance (MDR). The UIC2 monoclonal antibody recognizes human Pgp and inhibits its drug transport activity. However, this inhibition is partial, since UIC2 binds only to 10–40% of cell surface Pgps, while the rest becomes accessible to this antibody only in the presence of certain substrates or modulators (e.g. cyclosporine A (CsA)). The combined addition of UIC2 and 10 times lower concentrations of CsA than what is necessary for Pgp inhibition when the modulator is applied alone, decreased the EC50 of doxorubicin (DOX) in KB-V1 (Pgp+) cells in vitro almost to the level of KB-3-1 (Pgp-) cells. At the same time, UIC2 alone did not affect the EC50 value of DOX significantly. In xenotransplanted severe combined immunodeficient (SCID) mice co-treated with DOX, UIC2 and CsA, the average weight of Pgp+ tumors was only ∼10% of the untreated control and in 52% of these animals we could not detect tumors at all, while DOX treatment alone did not decrease the weight of Pgp+ tumors. These data were confirmed by visualizing the tumors in vivo by positron emission tomography (PET) based on their increased 18FDG accumulation. Unexpectedly, UIC2+DOX treatment also decreased the size of tumors compared to the DOX only treated animals, as opposed to the results of our in vitro cytotoxicity assays, suggesting that immunological factors are also involved in the antitumor effect of in vivo UIC2 treatment. Since UIC2 binding itself did not affect the viability of Pgp expressing cells, but it triggered in vitro cell killing by peripheral blood mononuclear cells (PBMCs), it is concluded that the impressive in vivo anti-tumor effect of the DOX-UIC2-CsA treatment is the combined result of Pgp inhibition and antibody dependent cell-mediated cytotoxicity (ADCC).
Highlights
One of the most common causes of cancer chemotherapy failure is the development of resistance against chemotherapeutic agents
In most cases the tumor cells are either intrinsically resistant, or become resistant in the course of chemotherapy, to a broad spectrum of chemotherapeutic agents, including compounds they have never met before [1]. This phenomenon is called multidrug resistance (MDR) and it is often associated with highlevel expression of active transporter proteins belonging to the ATP Binding Cassette (ABC) super-family, such as ABCB1 (MDR1, P-glycoprotein, Pgp), ABCC1 (MRP1, multidrug resistance protein 1) or ABCG2 (BCRP, breast cancer resistance protein)[2,3]
In previous studies we have demonstrated that the UIC2 antibody itself completely inhibits Pgp function when it is applied together with any of the above Pgp modulators added at low, sub-inhibitory concentrations [22]
Summary
One of the most common causes of cancer chemotherapy failure is the development of resistance against chemotherapeutic agents. In most cases the tumor cells are either intrinsically resistant, or become resistant in the course of chemotherapy, to a broad spectrum of chemotherapeutic agents, including compounds they have never met before [1] This phenomenon is called multidrug resistance (MDR) and it is often associated with highlevel expression of active transporter proteins belonging to the ATP Binding Cassette (ABC) super-family, such as ABCB1 (MDR1, P-glycoprotein, Pgp), ABCC1 (MRP1, multidrug resistance protein 1) or ABCG2 (BCRP, breast cancer resistance protein)[2,3]. The Pgp molecule consists of two almost identical halves connected by a 75 amino acid long intracellular linker region Both halves comprise six membrane spanning a-helices forming a transmembrane domain (TMD) and a nucleotide binding domain (NBD). The overall energy requirement of drug efflux is covered by ATP hydrolysis conducted by the two NBDs (for possible models, see e.g. Senior [5], Ambudkar et al [6])
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