Effect of nitric oxide on cytotoxicity of Taxol: enhanced Taxol transcellular permeability.
The present studies were aimed at testing the hypothesis that nitric oxide (NO) may enhance Taxol-induced cytotoxicity in carcinoma cells by increasing influx of Taxol into intracellular compartments. Prostate carcinoma cells (PC-3, LNCaP) and neuroblastoma cells (SKNDZ, CHP212) were used to investigate both transmembrane permeability and cytotoxicity of Taxol in the presence and absence of S-nitrosocaptopril (CapNO), a nitric oxide donating compound. The order of permeability rate of Taxol across the four cell lines was SKNDZ>LNCaP>PC-3>CHP212. Pretreatment of the cell lines with CapNO (100 microM) enhanced permeability of Taxol across prostate PC-3 and LNCaP cells, but not neuroblastoma SKNDZ and CHP212 cells. Taxol inhibited cell growth at nanomolar levels with IC(50)s of 0.21, 17.4, 96.4 and 842.9 nM corresponding to SKNDZ, PC-3, LNCaP and CHP212 cells, respectively. However, CapNO inhibited proliferation of the four cell lines at millimolar levels with IC(50)s ranging from 0.3 to 1.1 mM. Enhancing effect of CapNO (100 microM) on Taxol cytotoxicity were found in PC-3 and LNCaP cells, but not in SKNDZ and CHP212. The findings suggest that the cytotoxic potency of Taxol is mainly dependent upon the cell membrane permeabilization to Taxol, and the enhancing effect of CapNO on Taxol-induced cytotoxicity is primarily mediated via the increased influx of Taxol by NO into intracellular compartments, while NO-induced cytotoxicity cannot be excluded.
Jia
Lee
L
Cancer Therapy & Research Center, Institute for Drug Development, 14960 Omicron Dr., San Antonio, TX 78245-3217, USA. Jiale@mail.nih.gov
Schweizer
Julia
J
Wang
Yao
Y
Cerna
Cesario
C
Wong
Hong
H
Revilla
Marcus
M
D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000633:toxicity*
D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D017239:Paclitaxel