Sensitivity of committed hematopoietic progenitor cells in vitro (BFU-E, CFU-E, CFU-GM) and two human carcinoma cell lines toward rhodamine-123 and phosphonium salt II-41.
Lipophilic cationic compounds accumulate more rapidly in the mitochondria of many carcinoma-derived cells than in non-transformed cells, thus leading to their pronounced cytotoxic effects on carcinoma cells. In this report, in order to measure tumoricidal effects vs cytotoxicity to normal hematopoietic progenitors, we studied the sensitivity of committed human hematopoietic cells in vitro and two human carcinoma cell lines (2008 ovary carcinoma cells and HT29 colon cells) toward two such compounds, rhodamine-123 and phosphonium salt II-41. Continuous exposure of human marrow cells to rhodamine-123 or phosphonium salt II-41 for 7 and 14 days produced dose-related inhibition of colony formation of erythroid burst-forming units (BFU-E), erythroid colony forming units (CFU-E), and CFU-granulocyte/macrophage (CFU-GM). The average values of IC50 for several different human bone marrows are approximately 0.9-1.1 microM for rhodamine-123 toward BFU-E, CFU-E and CFU-GM, and 31-38 microM for phosphonium salt II-41 toward the same hematopoietic progenitors. These IC50 values are similar for each type of hematopoietic progenitors. In each case, rhodamine-123 appears to be at least 30-fold more growth suppressive than phosphonium salt II-41 in these in vitro colony assays. In addition, the sensitivity of these hematopoietic progenitors toward these two compounds is comparable to the inhibition of colony formation for the two human carcinoma cell lines. The lack of differences in the sensitivity among the various hematopoietic progenitors in vitro may disagree with previous studies showing there are vast differences in the state of cell cycle for these hematopoietic progenitor cells. However, these observations about the cytotoxicity in vitro can be explained by assuming that the cytotoxicity of these compounds depends on other factors such as differentiation processes, which result in the appearance of many or very active mitochondria. Alternatively, the lack of differences in the sensitivity of the in vitro colony formation can also be attributed to a reported decrease in expression of P-glycoprotein, a multidrug efflux pump, in the differentiating hematopoietic progeny cells.
Sehy
D W
DW
Department of Molecular & Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037.
Shao
L E
LE
Rideout
D
D
Yu
J
J
D003110:Colonic Neoplasms / Q000188:drug therapy*; D004354:Drug Screening Assays, Antitumor; D015672:Erythroid Precursor Cells / Q000187:drug effects; D005260:Female; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D020112:Rhodamine 123; D012235:Rhodamines / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured / Q000187:drug effects
D009943:Organophosphorus Compounds; D012235:Rhodamines; C080146:phosphonium salt II-41; D020112:Rhodamine 123