Chuang L F, Israel M, Chuang R Y
Department of Pharmacology and Toxicology, School of Medicine, University of California, Davis 95616.
Anticancer Res. 1991 Jul-Aug;11(4):1517-21.
Cremophor EL, a polyloxyethylene castor oil derivative used clinically as a parenteral vehicle, inhibits protein kinase c activity in vitro. The tumor promoting agent TPA (12-0-tetradecanoylphorbol-13-acetate) activated protein kinase C and induced phosphorylation of cellular proteins of human myeloblastic leukemia ML-1 cells. Polypeptides of 56 KDa, 44 KDa, 37 KDa, 35 KDa and 31 KDa were particularly phosphorylated in response to TPA activation. However, the phosphorylations of these polypeptides, especially that of 37 KDa, were greatly reduced by treatment of the TPA-activated ML-1 cells with Cremophor EL. Cremophor EL also inhibited the growth of ML-1 cells. On the other hand, the TPA-induced cell differentiation in ML-1, which is considered a separate event from protein kinase C activation, was not affected by Cremophor EL. These studies suggest biological implications for the observed in vitro activity of Cremophor EL. The studies may also provide a mechanism for the Cremophor EL-associated cytotoxicities observed when it is used clinically as a parenteral vehicle.
聚氧乙烯蓖麻油（Cremophor EL）是一种临床上用作肠胃外给药载体的聚氧乙烯蓖麻油衍生物，在体外可抑制蛋白激酶C的活性。肿瘤促进剂佛波酯（TPA，12-0-十四烷酰佛波醇-13-乙酸酯）可激活蛋白激酶C，并诱导人髓性白血病ML-1细胞的细胞蛋白磷酸化。响应TPA激活，56千道尔顿、44千道尔顿、37千道尔顿、35千道尔顿和31千道尔顿的多肽尤其会发生磷酸化。然而，用聚氧乙烯蓖麻油（Cremophor EL）处理TPA激活的ML-1细胞后，这些多肽的磷酸化，尤其是37千道尔顿多肽的磷酸化大大减少。聚氧乙烯蓖麻油（Cremophor EL）还抑制ML-1细胞的生长。另一方面，TPA诱导的ML-1细胞分化被认为是与蛋白激酶C激活分开的事件，不受聚氧乙烯蓖麻油（Cremophor EL）的影响。这些研究表明了聚氧乙烯蓖麻油（Cremophor EL）体外活性的生物学意义。这些研究还可能为聚氧乙烯蓖麻油（Cremophor EL）在临床上用作肠胃外给药载体时所观察到的细胞毒性提供一种机制。
