Mitochondrial targeting for photochemotherapy. Can selective tumor cell killing be predicted based on n-octanol/water distribution coefficients?
The concept of mitochondrial targeting for chemo- and photochemotherapy of neoplastic diseases has its origin in the observation that enhanced mitochondrial transmembrane potential is a common tumor cell phenotype. As a result of this enhanced transmembrane potential, a number of cationic dyes accumulate in larger amounts and are retained for longer periods in the mitochondria of tumor cells than in normal cells. Only a relatively small number of (photo)toxic dyes known to localize in energized cell mitochondria are capable of inducing the destruction of tumor cells with desirable degrees of selectivity, however. We investigated how lipophilic character may affect the degree of specificity with which cationic dyes localize in energized cell mitochondria and how mitochondrial specificity may affect tumor cell selectivity. To this end, we used fluorescence microscopy to characterize the subcellular localization of ethyl violet and seven analogs of the prototypical mitochondria-specific dye, rhodamine 123. All cationic rhodamines studied here (-0.62 < log D(ow) < 1.60, where D(ow) represents the n-octanol/water distribution coefficient) were found to show considerable mitochondrial specificity, while the more lipophilic ethyl violet (log D(ow) = 2.37) did not. Ethyl violet was found to localize not only in mitochondria, but also in lysosomes. We also compared the degree of selective tumor cell killing induced by ethyl violet and two phototoxic rhodamines, i.e., the dibromo derivatives of rhodamine 123 and its n-octyl ester analog. While ethyl violet induces the destruction of human uterine sarcoma (MES-SA) cells and normal green monkey kidney cells (CV-1) with comparable efficiency, the mitochondria-specific dibromorhodamines were found to induce the destruction of MES-SA cells with considerable selectivity. Our findings are consistent with the premise that mitochondrial localization per se does not provide successful selective tumor cell killing using mitochondrial targeting. Our results reinforce the hypothesis that while most cationic dyes can be expected to localize at least to some extent in energized cell mitochondria, only those showing virtually absolute mitochondrial specificity can actually mediate the destruction of tumor cells with desirable selectivity. These findings also support the hypothesis that the probability of success of mitochondrial targeting in photochemotherapy of neoplastic diseases is bound to be higher when the D(ow) associated with the drug candidate falls within approximately two orders of magnitude of that of rhodamine 123.
Belostotsky
I
I
Department of Chemistry and Biochemistry, University of Wisconsin, Milwaukee, Wisconsin 53211, USA.
da Silva
S M
SM
Paez
M G
MG
Indig
G L
GL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002412:Cations / Q000494:pharmacology; D004396:Coloring Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems; D005260:Female; D000882:Haplorhini; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D009369:Neoplasms / Q000188:drug therapy*; D010778:Photochemotherapy / Q000379:methods*; D020112:Rhodamine 123 / Q000494:pharmacology*; D012235:Rhodamines / Q000494:pharmacology*; D012394:Rosaniline Dyes / Q000494:pharmacology; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002412:Cations; D004396:Coloring Agents; D012235:Rhodamines; D012394:Rosaniline Dyes; D020112:Rhodamine 123; C034887:ethyl violet