br Drugs with documented pro apoptotic effects on platelets

Drugs with documented pro-apoptotic effects on platelets More than 200 drugs are reported to cause thrombocytopenia [5,42]. The concept of platelet apoptosis is relatively new and was only recently evaluated in the context of drug-induced thrombocytopenia [43]. Table 2 lists the drugs presently known to induce apoptosis in platelets. Below we provide a detailed review of the drugs' putative pro-apoptotic mechanisms, based on currently available experimental evidence.
Thrombocytopenia-inducing drugs: indirect evidence for pro-apoptotic activity Research from the past decade has revealed the importance of apoptosis in controlling platelet lifespan [13,92]. We have also gleaned considerable insight into apoptosis as a previously unidentified mechanism for drug-induced thrombocytopenia. This encourages speculation that other drugs known to cause platelet destruction, may in fact do so by promoting platelet apoptosis. For example, interleukin-2 (IL-2) therapy is associated with thrombocytopenia [93] and reportedly induces apoptosis in thymocytes [94] but this Tigecycline has not been evaluated in platelets. The platelet-destructive mechanisms of multiple drugs remain unknown [9]. It would therefore be of considerable interest to evaluate the effects of these drugs in the context of platelet apoptosis.
Perspectives
Acknowledgements The authors thank all members of the Kim laboratory and the UBC Centre for Blood Research, for helpful discussions. This work was supported, in part, by a Canadian Institutes of Health Research (CIHR) (grant number MC2-127872) Clinician-Scientist Salary Award (to H·K.).
Introduction Evodiamine (1), which is a quinazolinocarboline alkaloid, was first isolated from the fruits of Euodia rutaecarpa Bentham [1]. It exhibits diverse pharmacological activities, such as anti-Alzheimer's disease [2,3], anti-cancer [4], analgesic activities [5], anti-obesity [6], anti-hyperlipidemia [7] and anti-inflammation [8]. It also plays a vital role for preventing osteolytic diseases [9], reducing caffeine-induced sleep disturbances and excitation [10], ameliorating liver fibrosis via TGF-β1/Smad signaling pathway [11,12], and inhibiting angiotensin Ⅱ-induced cardiomyocyte hypertrophy [13]. Among them, the potential for evodiamine and its analogues as potent cancer chemotherapeutic agents has intrigued considerable research for new analogues with broad-spectrum antitumor activity [[14], [15], [16], [17]], including human hepatoma [18], urothelial cell carcinoma [19], renal carcinoma [20], lung cancer [21], nasopharyngeal carcinoma [22], leukemia [23], gastric cancer [24], oral cancer [25], colorectal cancer [26], pancreatic cancer [27], bladder cancer [28], breast cancer [29], and ovarian cancer [30]. Moreover, the mechanisms which have been investigated demonstrated that evodiamine could induce cell growth arrest and apoptosis in human urothelial cell carcinoma and renal carcinoma cells [19,20]. Treatment of hepatocellular carcinoma cells with evodiamine exerted antiproliferative activity by inducing Akt-mediated apoptosis and a WW (two conserved tryptophans) domain-containing oxidoreductase-dependent pathway [18,31]. Besides, western blot analysis indicated that evodiamine could mediate the up-regulation of apoptotic proteins Bax/Bcl-2 and cleaved-caspase 3 in hepatocellular carcinoma cells [18]. Whereafter, some researchers reported the effect of evodiamine on the interaction between DNA methyltransferases (DNMTs) and target microRNAs during malignant transformation of the colon by transforming growth factor-β1 (TGF-β1) [32]. Evodiamine showed broad antitumor activities through various mechanisms. However, moderate efficacy, as well as the poor selectivity between cancerous and normal cells, greatly impeded its further preclinical development and clinical applications. In order to overcome these disadvantages, novel evodiamine derivatives should be explored.