**10. References**

338 Advances in Cancer Therapy

nucleosome, and that this interaction is dependent upon phosphorylation of threonine 3 in histone H3's (Kelly et al., 2010; Wang et al., 2010). As this phosphorylation event is placed by the mitosis specific kinase, haspin, it is unclear whether such an interaction could occur in non-mitotic cells, however, indirect interactions in addition to direct binding between survivin and H2A also facilitates chromatin association (Kelly et al., 2010; Yamagishi et al., 2010), and borealin has been demonstrated to bind dsDNA directly in vitro (Klein et al., 2006). Hence, although not a transcription factor itself, it is indeed plausible that survivin

Despite its clear importance in cancer, strategies targeting survivin for oncotherapeutic gain have been rather elusive. The question posed here is whether "nuclear survivin" offers a unique therapeutic window? Now that it has been established that nuclear export is essential for activity of survivin as a tumour promoter, one possibility proposed by Stauber and colleagues, is the development of molecular decoys that interfere with its export by antagonising the NES(s). Potentially this strategy could be used to eliminate survivin and (re)sensitise tumours to current cancer therapies (Knauer et al., 2007; Stauber et al., 2007). Intriguingly in 2005, Otto and co-workers used a HLA-A2 restricted survivin peptide to vaccinate patients with advanced, stage IV melanoma. Serendipitously, the epitope selected was a peptide within the central NES of survivin, 96-104 (Colnaghi et al., 2006). Whether this peptide interfered with nuclear exportation of survivin in vivo was not addressed, but the treatment was well tolerated by patients and importantly it enhanced tumour cell apoptosis

We have taken a different angle, endeavouring to exploit the ability of survivin to accelerate cells into S-phase for therapeutic gain (Suzuki et al., 2000). In brief we infected cells with oncolytic viruses engineered to reproduce only in cells with a defective pRB pathway, in this case ovarian cancer cells. As viruses reproduce in S-phase of the host cell cycle, when we compared efficacy of cell lysis post-infection between control and survivin-NLS expressing cells, a marked increase in cytotoxicity was observed, suggesting that nuclear survivin expression synergised with oncolytic virus potency, to effectively eliminate cancer cells (Connell et al., 2008b). These data from cultured cells are promising, and given that survivin is an essential protein it is likely that its oncotherapeutic potential will be realised in

Survivin is a prosurvival factor that can promote S-phase entry; is essential for mitosis; whose presence renders cells resistant to apoptosis; and that is expressed at high levels almost universally in tumours. As a disease of inappropriate cell growth, cancer may arise through deregulated proliferation or failure to die in response to death inducing stimuli, and the success of therapeutic interventions is likely to be a case of tipping the balance between prosurvival and proapoptotic factors. For all these reasons the case for survivin as a novel anti-cancer target is compelling. The ability to dissect the pleiotropic functions of the protein apart by changes in its subcellular distribution may provide opportunities for

could indirectly modulate transcription.

and caused regression of metastatic lesions (Otto et al., 2005).

combination strategies like this, rather than as a target for a single agent.

therapeutic intervention and tailored targeting strategies.

**7. Clinical implications** 

**8. Concluding remarks** 


Nuclear Survivin: Cellular Consequences and Therapeutic Implications 341

Pettersen, E.F., T.D. Goddard, C.C. Huang, G.S. Couch, D.M. Greenblatt, E.C. Meng, and

Rexhepaj, E., K. Jirstrom, D.P. O'Connor, S.L. O'Brien, G. Landberg, M.J. Duffy, D.J.

Rodriguez, J.A., S.M.A. Lens, S.W. Span, G. Vader, R.H. Medema, F.A.E. Kruyt, and G.

Rodriguez, J.A., S.W. Span, C.G.M. Ferreira, F.A.E. Kruyt, and G. Giaccone. 2002. CRM1-

Ruchaud, S., M. Carmena, and W.C. Earnshaw. 2007. Chromosomal passengers: conducting

Stauber, R.H., W. Mann, and S.K. Knauer. 2007. Nuclear and cytoplasmic survivin:

Suzuki, A., M. Hayashida, T. Ito, H. Kawano, T. Nakano, M. Miura, K. Akahane, and K.

Takeno, S., S.-i. Yamashita, Y. Takahashi, K. Ono, M. Kamei, T. Moroga, and K. Kawahara.

Temme, A., P. Diestelkoetter-Bachert, M. Schmitz, A. Morgenroth, B. Weigle, M.A. Rieger,

Velculescu, V.E., S.L. Madden, L. Zhang, A.E. Lash, J. Yu, C. Rago, A. Lal, C.J. Wang, G.A.

Verdecia, M.A., H. Huang, E. Dutil, D.A. Kaiser, T. Hunter, and J.P. Noel. 2000. Structure of

Wang, H.J., M.P. Holloway, L. Ma, Z.A. Cooper, M. Riolo, A. Samkari, K.S.J. Elenitoba-

antiapoptotic protein survivin. *Experimental Cell Research*. 275:44-53.

cell division. *Nature Reviews in Molecular Cell Biology*. 8:798-812.

*Comput.Chem.* 25:1605-1612.

10:639-651.

25:4867-4879.

67:5999-6002.

3234.

37:440-445.

327:765-773.

388.

*Struct Biol*. 7:602-8.

285:36129-36137.

T.E. Ferrin. 2004. A visualization system for exploratory research and analysis. *J.* 

Brennan, and W.M. Gallagher. 2010. Validation of cytoplasmic-to-nuclear ratio of survivin as an indicator of improved prognosis in breast cancer. *BMC Cancer*.

Giaccone. 2006. Subcellular localization and nucleocytoplasmic transport of the chromosomal passenger proteins before nuclear envelope breakdown. *Oncogene*.

mediated nuclear export determines the cytoplasmic localisation of the

molecular mechanism, prognostic, and therapeutic potential. *Cancer Research*.

Shiraki. 2000. Survivin initiates cell cycle entry by the competitive interaction with Cdk4/p16INK4a and Cdk2/Cyclin E complex activation. *Oncogene*. 19:3225-

2010. Survivin expression in oesophageal squamous cell carcinoma: its prognostic impact and splice variant expression. *European Journal of Cardiac-Thoracic Surgery*.

A. Kiessling, and E.P. Rieber. 2005. Increased p21ras activity in human fibroblasts transduced with survivin enhances cell proliferation. *Biochem. Biophys. Res. Comm.*

Beaudry, K.M. Ciriello, B.P. Cook, M.R. Dufault, A.T. Ferguson, Y. Gao, T.-C. He, H. Hermeking, S.K. Hiraldo, P.M. Hwang, M.A. Lopez, H.F. Luderer, B. Mathews, J.M. Petroziello, K. Polyak, L. Zawel, W. Zhang, X. Zhang, W. Zhou, F.G. Haluska, J. Jen, S. Sukumar, G.M. Landes, G.J. Riggins, B. Vogelstein, and K.W. Kinzler. 1999. Analysis of human transcriptomes. *Nature Genetics*. 23:387-

the human anti-apoptotic protein survivin reveals a dimeric arrangement. *Nat* 

Johnson, Y.E. Chin, and R.A. Altura. 2010. Acetylation directs survivin nuclear localization to repress STAT3 oncogenic activity. *J. Biol. Chem.*


Connell, C.M., S.P. Wheatley, and I.A. McNeish. 2008b. Nuclear survivin abrogates

Dohi, T., F. Xia, and D.C. Altieri. 2007. Compartmentalized phosphorylation of IAP by

Engelsma, D., J.A. Rodriguez, A. Fish, G. Giaccone, and M. Fornerod. 2007.

Fortugno, P., N.R. Wall, A. Giodini, D.S. O'Connor, J. Plescia, K.M. Padgett, S. Tognin, P.C.

Fukuda, M., and L.M. Pelus. 2006. Survivin, a cancer target with an emerging role in normal

Kelly, A.E., C. Ghenoiu, J.Z. Xue, C. Zierhut, H. Kimura, and H. Funabiki. 2010. Survivin

Klein, U.R., E.A. Nigg, and U. Gruneberg. 2006. Centromere targeting of the chromosomal

Knauer, S.K., O.H. Kramer, T. Knosel, K. Engels, F. Rodel, K. A.F., W. Dietmaier, K.-H. L., N.

Li, F., J. Yang, N. Ramnath, M.M. Javle, and D. Tan. 2005. Nuclear or cytoplasmic expression

Li, J., M. Xing, M. Zhu, X.C. Wang, M. Wang, S. Zhou, N. Li, R. Wu, and M. Zhou. 2008.

Mahotka, C., J. Liebmann, M. Wenzel, C.V. Suschek, M. Schmitt, H.E. Gabbert, and C.D.

Mahotka, C., M. Wenzel, E. Springer, H.E. Gabbert, and C.D. Gerharz. 1999. Survivin-

Noton, E.A., R. Colnaghi, S. Tate, C. Starck, A. Carvalho, P.K. Ferrigno, and S.P.

Otto, K., M.H. Andersen, A. Eggert, P. Keikavoussi, L.O. Pedersen, J.C. Rath, M. Bock, E.-B.

adult tissues. *Mol. Cancer Therapy*. 5:1087-1098.

activity of survivin. *FASEB J.* 21:207-216.

terminal domain of INCENP. *Mol. Biol. Cell*. 17:2547-2558.

of survivin: What is the significance? *Int. J. Cancer*. 114:509-512.

in survivin nuclear localization. . *Cancer Letters*. 272:91-101.

survivin splice variants. *Cell Death Differ.* 9:1334-1342.

Aurora B. *Science*. 330:235-239.

protein kinase A regulates cytoprotection. *Molecular Cell*. 27:17-28.

68:7923-7931.

1502.

6102.

23:884-889.

*Chemistry.* 281:1286-1295.

115:575-585.

multiple cell cycle checkpoints and enhances virus oncolysis. *Cancer Research*.

Homodimerization antagonizes nuclear export of survivin. *Traffic*. 11:1495-

Marchisio, and D.C. Altieri. 2002. Survivin exists in immunochemically distinct subcellular pools and is involved in spindle microtubule function. *J.Cell Sci.*

Reads Phosphorylated Histone H3 Threonine 3 to Activate the Mitotic Kinase

passenger complex requires a ternary subcomplex of borealin, survivin, and the N-

Habtemichael, A. Schweitzer, J. Brieger, C. Rodel, W. Mann, I. Petersen, T. Heinzel, and R.H. Stauber. 2007. Nuclear export is essential for the tumour-promoting

Glycogen synthase kinase 3 beta induces apoptosis in cancer cells through increase

Gerharz. 2002. Differential subcellular localization of functionally divergent

{{Delta}}Ex3 and Survivin-2B: two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties. *Cancer Res.* 59:6097-

Wheatley. 2006. Molecular analysis of survivin isoforms: evidence that alternatively spliced variants do not play a role in mitosis. *J. Biological* 

Brocker, P. Strathen, E. Kampgen, and J.C. Becker. 2005. Lack of taxocity of therapyinduced T cell responses against the universal tumour antigen survivin. *Vaccine*.


**Part 3** 

**Promising Anticancer Plants** 


**Part 3** 

**Promising Anticancer Plants** 

342 Advances in Cancer Therapy

Xie, D., Y.X. Zeng, H.J. Wang, J.M. Wen, Y. Tao, J.S.T. Sham, and X.Y. Guan. 2006.

Yamagishi, Y., T. Honda, Y. Tanno, and Y. Watanabe. 2010. Two histone marks establish the inner centromere and chromosome bi-orientation. *Science*. 330:239-243.

glioblastoma. *British J. of Cancer*. 94:108-114.

Expression of cytoplasmic and nuclear survivin in primary and secondary human

**16**

*1Thailand 2USA* 

**Anticancer Properties of Curcumin**

*1Chulalongkorn University, Department of Pharmacology and Physiology* 

*Department of Basic Pharmaceutical Sciences, Morgantown, West Virginia* 

Curcumin is a major biological active compound from turmeric or *Curcuma longa*. This nontoxic natural compound has been reported to possess several biological activities that are therapeutically beneficial to cancer treatment. It has been reported to increase the efficacy of other chemotherapeutic agents and to reduce their toxic side effects which are the major drawback of most chemotherapeutic agents. Curcumin is also well known for its antiinflammatory activity (Amanda and Robert, 2008). Since cancer often develops under chronic inflammatory conditions, curcumin has the potential to be a preventive treatment agent against cancer. Furthermore, unlike most chemotherapeutic agents which act on a specific process of cancer development, i.e., cell growth or apoptosis, curcumin exerts its effect on various stages of cancer development, i.e., oncogene activation (Singh and Singh, 2009), cancer cell proliferation (Simon et al., 1998), apoptosis evasion (Han et al., 1999), anoikis resistance (Pongrakhananon et al., 2010), and metastasis (Chen et al., 2008) (Figure 1). Therefore, curcumin has the potential to overcome chemoresistance which is a major problem in cancer chemotherapy. This chapter will provide an overview of the anticancer activities of curcumin and present pre-clinical and clinical evidence supporting the use of

Cancer is known to be associated with genetic instability in which *c-myc* serves as a major modifier of many targeted genes (Mai and Mushinski, 2003). Likewise, the mutation of proto-oncogene *ras* has been identified in many types of tumor (Rajalingam et al., 2007). The dysregulation of these oncogenes is well recognized as an initial step in the development of tumorigenesis. Interestingly, curcumin has been reported to have a suppressive effect on the oncogenes and inhibit their downstream effectors such as cell cycle promoting and proapoptotic proteins (Singh and Singh, 2009). Curcumin also exhibits anticancer properties through its ability to inhibit cell proliferation and induce apoptosis. The anti-proliferative effect of curcumin is dependent on its concentration, duration of treatment, and specific cell type. At low doses, curcumin causes cell cycle arrest, while at higher doses it induces apoptosis. Cell proliferation is controlled by several cell cycle regulating proteins, notably the family of cyclin and cyclin-dependent kinases (Kastan and Bartek, 2004) whose expression is tightly associated with tumorigenesis (Diehl, 2002). Curcumin inhibits cell cycle progression by downregulating cyclin D1 and the transition from G1 to S phase in

**1. Introduction** 

curcumin as an anticancer agent.

Varisa Pongrakhananon1,2 and Yon Rojanasakul2

*Faculty of Pharmaceutical Sciences, Bangkok,* 

*2West Virginia University* 
