Effects of chemically modified tetracyclines (CMTs) in sensitive, multidrug resistant and apoptosis resistant leukaemia cell lines.
Recently discovered chemically modified tetracyclines (CMTs) have shown in vitro and in vivo anti-proliferative and anti-tumour activities. Here, we evaluated in vitro the anti-proliferative and apoptotic activity of six different dedimethylamino chemically modified tetracyclines (CMT-1, CMT-3, CMT-5, CMT-6, CMT-7 and CMT-8) in sensitive and multidrug resistant myeloid leukaemia cells (HL60 and HL60R) in vitro. Three of these compounds (CMT-5, CMT-6, CMT-7) showed low cytotoxic activity both in sensitive and in resistant cells, CMT-3 was endowed with a high anti-proliferative activity only in sensitive cells and was moderately effective as apoptosis inducing agent, with an activity similar to that shown by doxycycline. On the contrary, CMT-1 and CMT-8 were very effective as programmed cell death inducing agents. The apoptotic pathway activated by these compounds involved the activation of caspases, especially caspase-9 and, for CMT-1, also the activation of FAS: Interestingly CMT-8, but not CMT-1, was able to induce apoptosis in multidrug resistant HL60R and in Fas-ligand resistant HUT78B1 cell lines. These properties, together with others previously described (e.g. anti-metastatic and anti-osteolytic activities), suggest that CMT-8 may have important applications in the clinical management of cancer. The comparative analysis of structure-activity relationship of CMT-8 and doxycycline suggests that the C-5 hydroxy moiety may play an important role in conferring activity in multidrug resistant cells. These findings appear to support the hypothesis that CMT-8 may represent an interesting lead for the development of a new class of potent apoptosis inducer agents active in multidrug resistant and Fas-ligand resistant malignancies.
Tolomeo
M
M
Divisione di Ematologia e Servizio AIDS, Policlinico Universitario Paolo Giaccone, via del Vespro 129, 90127 Palermo, Italy.
Grimaudo
S
S
Milano
S
S
La Rosa
M
M
Ferlazzo
V
V
Di Bella
G
G
Barbera
C
C
Simoni
D
D
D'Agostino
P
P
Cillari
E
E
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007942:Leukemia, Experimental / Q000473:pathology*; D013754:Tetracyclines / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology
D000900:Anti-Bacterial Agents; D013754:Tetracyclines; D019014:fas Receptor; D020169:Caspases; D004318:Doxycycline