Figure 7
Figure 7. The interaction of PSGL-1 and P-selectin regulates drug resistance of MM cells induced by BMSCs and ECs in vitro and tumor progression in vivo. (A) MM1s cells (treated with vehicle, bortezomib 5nM, or dexamethasone 250nM) were cultured with or withoutBMSCs (treated with or without GMI-1070 500μM). Cell proliferation was measured at 24 hours by bromodeoxyuridine incorporation and ELISA. Coculture of MM1s with BMSCs induced resistance to both bortezomib and dexamethasone in MM1s cells which was reversed by GMI-1070. Data represent means ± SD of triplicate experiments. (B) MM1s cells (treated with vehicle, bortezomib 5nM or dexamethasone 250 nM) were cultured with or without the presence of HUVECs (treated with or without GMI-1070 500μM). Cell proliferation was measured at 24 hours by bromodeoxyuridine incorporation and ELISA. Coculture of MM1s with HUVECs induced resistance to both bortezomib and dexamethasone in MM1s cells that was reversed by GMI-1070. Data represent means ± SD of triplicate experiments. (C) Effect of inhibition of the interaction of PSGL-1 with P-selectin by GMI-1070 on the sensitivity of MM tumors to bortezomib in vivo. SCID mice (n = 10 per group) were injected with MM1s cells engineered to express luciferase and tumor growth was determined by bioluminescence imaging. Mice were divided in 4 groups: (1) the control group, which received weekly IP injection of vehicle and were implanted with pumps loaded with vehicle every 2 weeks (for 4 weeks); (2) the GMI-1070–treated group, which received weekly IP injection of vehicle and were implanted with a pump loaded with 200 μL of 150 mg/mL of GMI-1070 that was changed every 2 weeks (for 4 weeks); (3) the bortezomib-treated group, which received weekly IP injection of bortezomib 1.5 mg/kg and were implanted with a pump loaded with vehicle that was changed every 2 weeks (for 4 weeks); and (4) the combination group, which received weekly IP injection of bortezomib 1.5 mg/kg and were implanted with a pump loaded with 200 μL of 150 mg/mL GMI-1070 that was changed every 2 weeks (for 4 weeks). Tumor progression was detected using bioluminescence. Treatment with GMI-1070 alone did not affect the tumor progression, but it increased the sensitivity of MM cells to bortezomib, and decreased tumor progression was observed in the group treated with a combination of GMI-1070 and bortezomib compared with bortezomib alone (P < .01). (D) Kaplan-Meier curves of survival of groups 1 through 4 described in panel C. Increased survival was observed in mice treated with the combination of GMI-1070 and bortezomib compared with bortezomib alone, (P = .012).

The interaction of PSGL-1 and P-selectin regulates drug resistance of MM cells induced by BMSCs and ECs in vitro and tumor progression in vivo. (A) MM1s cells (treated with vehicle, bortezomib 5nM, or dexamethasone 250nM) were cultured with or withoutBMSCs (treated with or without GMI-1070 500μM). Cell proliferation was measured at 24 hours by bromodeoxyuridine incorporation and ELISA. Coculture of MM1s with BMSCs induced resistance to both bortezomib and dexamethasone in MM1s cells which was reversed by GMI-1070. Data represent means ± SD of triplicate experiments. (B) MM1s cells (treated with vehicle, bortezomib 5nM or dexamethasone 250 nM) were cultured with or without the presence of HUVECs (treated with or without GMI-1070 500μM). Cell proliferation was measured at 24 hours by bromodeoxyuridine incorporation and ELISA. Coculture of MM1s with HUVECs induced resistance to both bortezomib and dexamethasone in MM1s cells that was reversed by GMI-1070. Data represent means ± SD of triplicate experiments. (C) Effect of inhibition of the interaction of PSGL-1 with P-selectin by GMI-1070 on the sensitivity of MM tumors to bortezomib in vivo. SCID mice (n = 10 per group) were injected with MM1s cells engineered to express luciferase and tumor growth was determined by bioluminescence imaging. Mice were divided in 4 groups: (1) the control group, which received weekly IP injection of vehicle and were implanted with pumps loaded with vehicle every 2 weeks (for 4 weeks); (2) the GMI-1070–treated group, which received weekly IP injection of vehicle and were implanted with a pump loaded with 200 μL of 150 mg/mL of GMI-1070 that was changed every 2 weeks (for 4 weeks); (3) the bortezomib-treated group, which received weekly IP injection of bortezomib 1.5 mg/kg and were implanted with a pump loaded with vehicle that was changed every 2 weeks (for 4 weeks); and (4) the combination group, which received weekly IP injection of bortezomib 1.5 mg/kg and were implanted with a pump loaded with 200 μL of 150 mg/mL GMI-1070 that was changed every 2 weeks (for 4 weeks). Tumor progression was detected using bioluminescence. Treatment with GMI-1070 alone did not affect the tumor progression, but it increased the sensitivity of MM cells to bortezomib, and decreased tumor progression was observed in the group treated with a combination of GMI-1070 and bortezomib compared with bortezomib alone (P < .01). (D) Kaplan-Meier curves of survival of groups 1 through 4 described in panel C. Increased survival was observed in mice treated with the combination of GMI-1070 and bortezomib compared with bortezomib alone, (P = .012).

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