Therapeutics
Continued from page 39
13 Chen, DJ, Huerta, S. Smac mimetics as new cancer therapeutics. Anticancer Drugs. 2009 Sep;20(8):646-58. 14Tamm, I, Kornblau, SM, Segall, H, Krajewski, S, Welsh, K, Kitada, S, Scudiero, DA, Tudor, G, Qui, YH, Monks, A, Andreeff, M, Reed, JC. Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res. 2000 May;6(5):1796-803. 15 Mizutani, Y, Nakanishi, H, Yamamoto, K, Li, YN, Matsubara, H, Mikami, K, Okihara, K, Kawauchi, A, Bonavida, B, Miki, T. Downregulation of Smac/DIABLO expression in renal cell carcinoma and its prognostic significance. J Clin Oncol. 2005 Jan 20;23(3):448- 54. Epub 2004 Nov 30. 16 Mizutani, Y, Nakanishi, H, Yamamoto, K, Li, YN, Matsubara, H, Mikami, K, Okihara, K, Kawauchi, A, Bonavida, B, Miki, T. Downregulation of Smac/DIABLO expression in renal cell carcinoma and its prognostic significance. J Clin Oncol. 2005 Jan 20;23(3):448- 54. Epub 2004 Nov 30. 17 Kempkensteffen, C, Jäger, T, Bub, J, Weikert, S, Hinz, S, Christoph, F, Krause, H, Schostak, M, Miller, K, Schrader, M. The equilibrium of XIAP and Smac/DIABLO expression is gradually deranged during the development and progression of testicular germ cell tumours. Int J Androl. 2007 Oct;30(5):476-83. Epub 2007 Feb 12. 18 Bao, ST, Gui, SQ, Lin, MS. Relationship between expression of Smac and Survivin and apoptosis of primary hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2006 Nov;5(4):580-3.
the constitutive activation of NF-B and chronic inflammation play a major role in tumour devel- opment, particularly lymphomas, leukaemias and many solid tumours7-9.
The pro-apoptotic mechanism of Smac Smac – endogenous IAP antagonist and caspase activator
Smac (second mitochondria-derived activator of caspase), also known as DIABLO (direct inhibitor of apoptosis protein-binding protein with low pI), is a pro-apoptotic mitochondrial protein that is released upon apoptotic stimuli into the cyotosol and binds to the IAPs10,11. Smac antagonises IAP- mediated caspase inhibition by direct inhibition and/or induces proteasomal degradation of some members of the IAP family (cIAP1 and cIAP2). A study published in 2000 by Yigong Shi’s laborato- ry at Princeton University described the structural and biochemical basis of apoptotic activation by Smac12. Smac homodimerises and forms a stable protein dimer. The ability of SMAC to promote both the proteolytic activation of pro-caspase-3 and the enzymatic activity of mature caspase-3 depends on its ability to specifically interact with XIAP. Smac binds to the BIR1/BIR2 linker region and BIR-3 of XIAP disrupting the inhibition of cas- pase-3 and -7 and preventing cell death1,13. Smac and Smac mimetics induce proteasomal degradation of cIAP1 and cIAP2 resulting in inhi- bition of the canonical pathway and activation of the non-canonical pathway via NIK stabilisation.
IAPs, Smac and cancer Continued on page 41 40
Increased expression of IAPs is found in many types of human cancers and is associated with chemoresistance, disease progression and poor prognosis. In vitro, higher expression of IAPs pro- motes resistance to chemotherapy agents as well as radiation. In acute myeloid leukaemia, higher expression of XIAP may lead to a poorer progno- sis14. IAPs protect tumour cells from the cytotoxic effects of cancer-related inflammation induced by TNF or TRAIL that are prevalent in the tumour microenvironment of many tumours. Therefore, a therapeutic approach that results in the degrada- tion of cIAPs and/or antagonism of XIAP could promote the lethal effects of TNF on cancer cells while shutting down the survival pathway mediat- ed by TNF driven NF-B expression. Preclinical studies have shown that Smac expres- sion can be an important factor in determining a cancer cell’s sensitivity to undergo apoptosis when induced by a variety of apoptotic stimuli. Several studies have shown that reduced expression of
Smac is associated with cancer progression. For example, Mizutani et al showed that Smac expres- sion was downregulated in renal cell carcinoma (RCC), and an absence of Smac protein expression predicted worse outcomes in RCC15. Another study showed that RCC patients with low Smac mRNA expression had a four-times higher risk of dying from RCC than those with high expres- sion16,17. Additionally, testicular tumours with a more advanced malignant phenotype showed lower Smac mRNA expression levels. The mRNA as well as protein expression was reduced in hepa- tocellular carcinoma (HCC) when compared to normal hepatic tissue18.
The fact that overexpression of Smac sensitises neoplastic cells to apoptosis19, together with the importance of the role played by Smac and IAPs in regulating apoptosis in tumour cells, became the rationale for the design and development of Smac mimetics as a new class of cancer therapeutics.
Smac mimetics – a novel class of therapeutics regulating apoptosis and NF-B
The discovery of Smac mimetics or IAP antagonists was enabled by the elucidation of the crystal struc- ture of the interaction between Smac and IAPs12. Smac mimetics facilitate apoptotic cell death in tumour cells through multiple mechanisms: they bind and antagonise IAPs and reactivate the apop- totic pathway; Smac mimetics can eliminate IAPs by promoting autoubiquitylation and proteasomal degradation of cIAPs; and they activate the cell’s extrinsic apoptotic pathway by autocrine TNF stimulation or when TNF or TRAIL are present in the tumour microenvironment. Interestingly, the induction of apoptosis is highly specific for suscep- tible tumours and spares normal tissue. In tissue culture, Smac mimetics are capable of killing tumour cells in the picomolar concentration range while having no effect on normal cells in the 100 micromolar range. This marked selectivity is thought to be a result of elevated levels of key cas- pases in tumour cells.
Several Smac mimetics have been developed that have demonstrated good anti-tumour activity in pre- clinical studies. Bivalent Smac mimetics are signifi- cantly more potent than monovalent Smac mimetics generally have improved pharmacokinetics. Bivalent mimetics have a higher molecular weight and may require a parenteral administration13. Of those Smac mimetics that have entered the clinic, the most advanced is TL32711, a potent bivalent small molecule Smac mimetic. Preclinical studies in patient-derived tumour xenotransplant
Drug Discovery World Fall 2011
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