**14.4. Necroptosis**

94 Apoptosis and Medicine

trails [110].

[195,196].

proinflammatory NFkB pathway [102].

**14.3. DNA damage and cell cycle** 

has recently entered clinical trials [78].

*IAP inhibitors and Smac mimetics:* Moreover, the role of IAPs in regulating apoptosis and/or necroptosis has led to the development of small molecules that antagonize IAP, or mimic the function of Smac/DIABLO. In fact, IAPs have been found to be overexpressed in many cancers and to be associated with poor prognosis and chemoresistance [102], making them putative targets for cancer therapeutics. Smac mimetics can sensitize chemoresistant cancer cells to cisplatin, doxorubicin or TRAIL [190], either as single agents or in combination with other drugs [109]. Therefore, some of these agents (AT-406, LCL-161, HGS-1029, TL32711, GDC-0917) [73] have recently entered clinical trials [191] for the treatment of solid tumours and lymphomas [192]. However, the potential of Smac mimetics as antitumour agents has been questioned, since the inhibition of cIAP1 and cIAP2 can stabilize IKK and activate the

Other IAP-targeted therapies such as XIAP and survivin antisense oligonucleotides have been developed [102]. Antisense oligonucleotides against survivin synergize with etoposide in non small lung cancer cells [117]. LY2181308 is a second generation antisense oligonucleotide being evaluated in clinical trials. In addition, a small molecule inhibitor of survivin, YM155, has shown potency in preclinical models and has entered phase II clinical

*p53 inhibitors:* Since p53 is frequently mutated in tumours, therapeutic approaches have been made to restore p53 function. Since p53 is targeted to degradation through interaction with mdm2, some drugs such as RITA, Nutlin-3 or HLI198 have been designed to disrupt p53 mdm2 interaction. These compounds bind to the p53 binding site on mdm2 or inhibit mdm2 ubiquitin ligase activity. This approach is valid in cancers with wild type p53, such as haematological malignancies [56]. A second approach is to rescue wild-type 53 function in p53-mutated tumours. PRIMA-1 restores sequence-specific DNA binding and active conformation of mutant p53 proteins. PRIMA-1 can synergize with conventional chemotherapeutic drugs and inhibit tumour growth in mice with no apparent toxicity and

*Chk1/2 inhibitors:* The concept of "synthetic lethality" coined by Kaelin, by which two molecular lesions combine to have a lethal effect on the cell, although neither of them is harmful individually, has recently gained interest [193,194]. In this context, Chk inhibitors may have a therapeutic potential in p53-mutated tumours. UCN-01, the first Chk inhibitor evaluated in humans, has limited clinical value due to its toxicity. Other Chk inhibitors functioning as checkpoint abrogators that are being evaluated in clinical trials are: AZD7762, LY26303618, CBT501, PF-00477736, SCH 900776, XL844, and the wee-1 inhibitor MK-1775

*PARP inhibitors:* Other example of synthetic lethality is BRCA mutant breast cancer. BRCA1 and BRCA2 play a role in homologous recombination, an important repair pathway for *cFLIP*: This antiapoptotic regulator is expressed as long (c-FLIPL) short (c-FLIPS) or c-FLIPR variants in human cells. In the absence of cFLIP, the ripoptosome triggers apoptotic cell death. On the contrary, expression of cFLIPL, which binds caspase-8, neutralizes its ability to engage the apoptotic machinery, but inhibits necroptosis by preventing RIP1-RIP3 association. On the other hand, c-FLIPS, although is able to bind caspase-8, does not form an active heteromer and necroptosis can develop [78,199]. Increased expression of c-FLIP has been found in several human cancers and is associated with poor prognosis [102]. Downregulation of FLIP seems to be a promising therapeutic strategy. Research efforts are being focused on the development of small interference RNA (siRNA) targeted against c-FLIP. In addition, several antitumour agents can downregulate c-FLIP at the transcriptional or posttranscriptional level [200].
