Effects of chemically modified tetracyclines (CMTs) in sensitive, multidrug resistant and apoptosis resistant leukaemia cell lines

Abstract

1 Recently discovered chemically modi®ed 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 di erent dedimethylamino chemically modi®ed 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. 2 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 e ective as apoptosis inducing agent, with an activity similar to that shown by doxycycline. On the contrary, CMT-1 and CMT-8 were very e ective as programmed cell death inducing agents. 3 The apoptotic pathway activated by these compounds involved the activation of caspases, especially caspase-9 and, for CMT-1, also the activation of Fas. 4 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. 5 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 ®ndings 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.

A novel non‐antibacterial, non‐chelating hydroxypyrazoline derivative of minocycline inhibits nociception and oedema in mice

“…The chemically modified tetracyclines (CMTs), devoid of antibacterial activity, also attenuate some manifestations of the inflammatory response (Patel et al, 1999;D'Agostino et al, 2001;Sandler et al, 2005). Furthermore, some CMTs induce apoptosis in multidrug-and apoptosis-resistant leukaemia cell lines, and these effects underlie their potential antitumour activity (Tolomeo et al, 2001). Indeed, the efficacy and safety of incyclinide, also known as CMT-3, have been evaluated in clinical trials for the treatment of acne and some types of cancer (www.clinicaltrials.gov).…”

Antibiotic or Anti-inflammatory Agent? The Double-Edged Sword of Tetracyclines

“…The apoptotic activity of CMTs has been proposed to be related to the absence of the 4-dimethylamino group at the carbon atom [44]. The induction of apoptosis by CMTs has been reported in several different cell types and disease models [43][44][45][46][47]. It has been suggested that CMTs induce mitochondria-mediated apoptosis through both caspasedependent and -independent pathways.…”

“…They induce typical morphological changes, increase the activity of several caspases, increase the level of cytosolic cytochrome c and change the balance of Bax/Bcl-2 protein expression [43][44][45][46][47][48]. Tetracyclines have been shown to induce apoptosis of many immune system cells such as mast cells [47], T lymphocytes [49] and macrophages [43].…”

“…Onoda et al [46] report that the doxycycline-induced apoptotic changes were observed delayed in comparison to CMT-3. The apoptotic activity of CMTs has been proposed to be related to the absence of the 4-dimethylamino group at the carbon atom [44]. The induction of apoptosis by CMTs has been reported in several different cell types and disease models [43][44][45][46][47].…”

Exploring the Nature of the Nanocavity and Channels in Apoferritin and Apoferritin–Sodium Dodecyl Sulfate Complex Using an Enhanced Antenna Effect through the Encapsulation of EuIII–Tetracycline

“…Herein, we report the encapsulation of tetracycline (TC), an antibiotic, within the apoferritin cavity owing to the recent implications of the cytostatic and cytotoxic capacities of TC on tumor cells of many different origins, both in vitro and in animal models . It would also be worthwhile if the apoferritin–TC complex could be tracked within the biological system.…”