Our previous studies support a protective role of the transcriptional activity of p53 in response to mitotic spindle damage. Down-regulation of p53 could result in a sensitization to PTX as a consequence of prevention of p21WAF1/Cip1 induction in response to PTX. Indeed, we have found that ovarian carcinoma cells selected for resistance to cisplatin and characterized by mutational inactivation of p53 are hypersensitive to PTX. The results presented in this study indicated that ST2782 prevented the upregulation of p21WAF1/Cip1 induced by both PTX, a microtubule polymerising agent and vinorelbine, a microtubule depolymerising agent. The modulation of p21WAF1/Cip1 expression in PTX-treated cells by ST2782 is reminiscent of the effect of pifithrin-a,a transcriptional inhibitor of p53. Relevant to this point is the observation that, in contrast to SAHA, ST2782 and ST3595 induced a dose-dependent down-regulation of p53. The mechanism of this effect is not clearly understood, but likely it is related to modulation of acetylation status of Hsp90, which, as is a protein substrate for the cytoplasmic HDAC6 isoenzyme, may be involved in p53 stabilization. The sensitization of wild-type p53 cells in vitro to PTX by ST3595 was confirmed in tumor xenograft models. The enhancement of the PTX antitumor efficacy by ST3595 was impressive in the osteosarcoma model resulting in complete tumor regression in all treated animals, without evidence of disease at the end of the experiment. These preclinical findings may have therapeutic implications also considering the use of BAY-60-7550 molecular weight nontoxic doses of PTX and the good tolerability of ST3595 following protracted oral administration. In conclusion, given the current interest for combination therapy with HDACi, the present study provides a basis for a rational strategy to improve the taxane-based antitumor therapy. Protein C inhibitor is a 57 kD glycoprotein that belongs to the serine protease inhibitor superfamily of proteins, and exists in many tissues and fluids in humans, including reproductive organs, semen, blood, urine, breast milk and skin. PCI found in blood originates from the liver and is capable of inhibiting several serine proteases involved in the regulation of coagulation and fibrinolysis, including activated protein C, thrombin, factor Xa, various kallikreins and plasminogen activators. Additionally, PCI has been found to have antimicrobial and antitumor properties and thus appears to be a medically interesting versatile protein. PCI has been identified both in the human male and female reproductive tracts. The concentration of PCI in follicular fluid is similar to that in plasma. In contrast, a 40-fold higher concentration is present in the Adriamycin Seminal plasma. Seminal plasma PCI is mainly synthesized in seminal vesicles, where it undergoes glycosylation and is subsequently secreted in an active form. After ejaculation, it is inactivated by forming complexes with prostate-specific antigen, t-PA, u-PA, and tissue kallikrein. Although the function of PCI in seminal plasma is not yet completely understood, evidence showing that PCI plays a significant role in male fertility has been published. PCI knock-out mice appear to be healthy but males of this genotype are infertile due to abnormal spermatogenesis as the Sertoli cell barrier is destroyed. In a clinical investigation, the inhibitory activities of PCI towards u-PA and tPA were absent in two infertile patients, suggesting that formation of PCI complexes with u-PA and t-PA plays a role in fertilization in the human. Given that the physiological role of PSA is the degradation of the major proteins of seminal coagula, Semenogelin-I and Sg-II, PCI also appears to be involved in the regulation of semen.