The Strong In Vivo Anti-Tumor Effect of the UIC2 Monoclonal Antibody Is the Combined Result of Pgp Inhibition and Antibody Dependent Cell-Mediated Cytotoxicity

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).

Ceritinib Enhances the Efficacy of Substrate Chemotherapeutic Agent in Human ABCB1-Overexpressing Leukemia Cells In Vitro, In Vivo and Ex-Vivo

“…Previous studies have shown that activation of the AKT and ERK1/2 pathways resulted in the resistance to anti-cancer drugs in tumor cells [31, 32]. To determine whether the reversal MDR by ceritinib linked to the blockage of phosphorylation status of AKT and ERK1/2 in K562/adr cells and their parental cells, we examined the total and phosphorylation levels of AKT and ERK1/2 after concentration and time-dependently treating the cells with ceritinib.…”

Role of ABCB1 in mediating chemoresistance of triple-negative breast cancers

“…demonstrated that UIC2 can inhibit the pumping activity of Pgp and its inhibitory effect is equal to some Pgp inhibitors, such as verapamil, at its highest clinical concentration [ 82 ]. Another study [ 84 ] showed that UIC2 has the ability to bind only to 10–40% of cell surface Pgp, whilst, its ability to bind the rest increases in presence of Pgp substrates or modulators. The investigators found that in vitro combination of UIC2 with Cyclosporine, at ten-fold lower concentration than that used for Pgp inhibition, decreased the EC 50 value of doxorubicin in KBV1 (Pgp+) cells to the same level of KB31 (Pgp−) cells [ 84 ].…”

“…Another study [ 84 ] showed that UIC2 has the ability to bind only to 10–40% of cell surface Pgp, whilst, its ability to bind the rest increases in presence of Pgp substrates or modulators. The investigators found that in vitro combination of UIC2 with Cyclosporine, at ten-fold lower concentration than that used for Pgp inhibition, decreased the EC 50 value of doxorubicin in KBV1 (Pgp+) cells to the same level of KB31 (Pgp−) cells [ 84 ]. These results were consistent with in vivo studies in immunodeficient mice, which showed a significant decrease in Pgp + tumor weight when treated with a combination of doxorubicin and UIC2 compared with doxorubicin alone [ 84 ].…”

“…The investigators found that in vitro combination of UIC2 with Cyclosporine, at ten-fold lower concentration than that used for Pgp inhibition, decreased the EC 50 value of doxorubicin in KBV1 (Pgp+) cells to the same level of KB31 (Pgp−) cells [ 84 ]. These results were consistent with in vivo studies in immunodeficient mice, which showed a significant decrease in Pgp + tumor weight when treated with a combination of doxorubicin and UIC2 compared with doxorubicin alone [ 84 ]. Although, this strategy appears to be promising, currently no studies using TNBC models have been performed to ascertain its utility in overcoming Pgp-mediated MDR in TNBCs.…”