However, observations showing that saquinavir could enhance c-Myc and possibly hTERT protein expression at least in part through proteasome activity inhibition seem to contrast the hypothesis that this agent could increase target cell immunogenicity. In fact, the presence of large amounts of immunogenic peptides requires substantial protein degradation via ubiquitin-proteasome system. Nevertheless, it is reasonable to assume that drug-induced protein accumulation could be followed by a “rebound” phenomenon, with augmented hTERT degradation and increased

levels of hTERT-derived immunogenic peptides in target cells upon saquinavir withdrawal. Indeed, this type of antigen presentation kinetics is currently

under investigation in our laboratory. The observation that saquinavir increases c-Myc levels is in line with the finding that the drug is able to induce apoptosis [7, https://www.selleckchem.com/products/stattic.html 11]. Actually, c-Myc possesses a crucial function in controlling cell growth, differentiation and apoptosis, while its abnormal expression is associated with many tumors. Overexpression of c-Myc has been shown to sensitize tumor cells to ATM inhibitor apoptosis by amplifying the intrinsic mitochondrial pathway and by triggering the death receptor pathways by a variety of stimuli [37]. Therefore an hypothesis is that the intracellular accumulation of possibly polyubiquinated c-Myc following the saquinavir-mediated inhibition of the proteasome, could contribute to explain the mechanism underlying the apoptosis observed in different

tumor cell models treated with the protease inhinibitor [7, 11] and is currently under investigation. Conclusions In conclusion, the present report shows for the first time that saquinavir is able to increase telomerase activity in leukaemia T cells, thus extending a similar finding previously obtained by us in normal haemopoietic cells to the area of haemato-oncology. Moreover, this study indicates c-Myc as molecular target of saquinavir, suggesting new perspectives in the pharmacological applications of PIs. On the other hand, in accordance with previous old reports showing antitumor activity of saquinavir, we confirmed that the drug does not enhance but rather inhibited the growth of leukaemic cells. Therefore, saquinavir appears to play an attracting role as a potential antitumor agent, since along with its inhibiting effect on cell proliferation it could provide a novel strategy for increasing malignant cell immunogenicity. Acknowledgments This work was supported by “IV Progetto AIDS” (Istituto Superiore di Sanità), “Alleanza Contro il Cancro” (Istituto superiore di Sanità) to OF and by “Programma di Ricerca Scientifica di rilevante interesse Nazionale”, MIUR-2008 to AA. We would like to thank Dr. Anna Giuliani for her technical selleck chemicals assistance in preparing the manuscript. References 1.