Figure 4.

Verapamil and MDM2–p53 antagonists Nutlin-3, NDD0005 and MI-63 increase intracellular vincristine levels in high MDR-1-expressing neuroblastoma cells but not in low MDR-1-expressing cells. Intracellular levels of vincristine in (A) SKNBe2C, (B) SHSY5Y and (C) SKNAS cells treated for 8 h with 1 × or 5 × their respective 72-h vincristine GI₅₀ concentrations (SKNBe2C 32.8/164 nM; SHSY5Y 8.2/41 nM; SKNAS 1.5/7.5 nM) alone or in combination with 2 μM verapamil, Nutlin-3, NDD0005, MI-63 or RG7388. Data are expressed relative to cells treated with 1 × vincristine GI₅₀ concentration alone. Data are shown as the average of at least three independent experiments±s.e.m. (D) Western blot analysis showing MDR-1 and p53 expression in SKNBe2C, SKNAS and SHSY5Y cells after treatment with 2 μM each of verapamil, NDD0005, Nutlin-3, MI-63 or RG7388 for 8 h.