Evaluating the cell killing effect of WYT1-70-6 in combination with clinical

Chapter 3. Results

3.6. Evaluating the cell killing effect of WYT1-70-6 in combination with clinical

Doxorubicin is a clinically used chemo drug for treating multiple myeloma. In ad-dition, doxorubicin is also widely used for treating an array of cancer types, including bladder, breast, and the lung. We thus assessed the cell killing effect of combination therapy using WYT1-70-6 and doxorubicin in the multiple myeloma RPMI 8226 cells.

The combination of these two agents displayed a more potent cytotoxicity than either of them used alone (Fig. 16A). However, these two agents did not exhibit significant additive interaction according to the isobologram analysis (Steel and Peckham, 1979).

In contrast, the proteasome inhibitor bortezomib, is a FDA-approved drug for treating multiple myeloma. The recent research revealed that bortezomib actually ac-tivates the NF-κB signaling pathway (Hideshima et al., 2009). The studies indicated the fact that bortezomib-induced cytotoxicity is not associated with NF-κB inhibition in multiple myeloma. Therefore, we assumed a combination therapy using bortezomib and WYT1-70-6 would have a synergistic cell killing effect. The result showed that this combination treatment displayed an additive interaction as judged by MTS assay

(Fig. 16B). To examine this additive interaction between bortezomib and WYT1-70-6, we harvested cell lysates treated for 8 h with bortezomib alone or in combination in the RPMI 8226 cells. As shown in Figure 17, cells treated with bortezomib (lane 2) exhibited lower protein level of IκBα than that of the solvent control (lane 1). Moreo-ver, results from the Western blots of the nuclear p65 were consistent with this obser-vation (Fig. 17B). Our data suggested that bortezomib induced the degradation of IκBα and consequently the nuclear translocation of p65 in RPMI 8226 cells. On the other hand, bortezomib in combination with WYT1-70-6 inhibited NF-κB activation (Fig 17A, lane 3) in the same cell line. Taken together, this immunoblotting result supports the additive interaction between bortezomib and WYT1-70-6 in the MTS assay and suggests a more effective therapeutic option by combination therapy using bortezomib and WYT1-70-6 in multiple myeloma.

Discussion

4.1. Marine microorganism Zooshikella sp., a new source of prodiginine family In this study, we demonstrated a natural product, prodigiosin, extracted from the marine microorganisim Zooshikella sp. and exhibiting NF-κB inhibitor and anticancer property through a series of experiments. This new species of the genus Zooshikella is gram-negative marine bacterium which was identified as a new source of prodiginine family, including two structures which were unknown before (Lee, Kim et al. 2011).

4.2. Prodigiosin has gotten attention again as an anticancer agent in recent years Although the discovery of prodigiosin was very early, it was regarded as antibiotics at that time (Lichstein and Van De Sand 1946). During these two decades, scientists have perceived that prodigiosin may have other applications. The new characteristics was identified that prodigiosin represses the growth of lymphocytes, especially T-cells, which displays a potential to be an immunosuppressant (Nakamura, Nagai et al. 1986; Magae, Yamashita et al. 1993; Han, Kim et al. 1998). Furthermore, the studies from 2000s revealed that prodigiosin can induce apoptosis in cancer cell lines (Montaner and Perez-Tomas 2001; Montaner and Perez-Tomas 2002; Llagostera, Soto-Cerrato et al. 2003). However, most of these studies only indicated that prodigiosin results in apoptosis through caspase-dependent pathway. In recent re-searches, more characteristics of prodigiosin have been clarified, including antiproliferation, inducing DNA damage and inhibiting the function of topoisomerase I and II (Montaner, Castillo-Avila et al. 2005; Hsieh, Shieh et al. 2012). Thus, those recent studies suggest that prodigiosin induces apoptosis through modulating several pathways as well as damaging DNA directly. And results from this thesis study also support the previous researches about the characteristics of prodigiosin.

4.3. Prodigiosin inhibits NF-κB signaling pathway in cancer cells

Previous studies on prodigiosin associated with NF-κB signaling pathway were fo-cused on primary culture of immunocytes for demonstrating its immunosuppressive property (Mortellaro, Songia et al. 1999; Huh, Yim et al. 2007). However, there were no reports that prodigiosin inhibits the activation of NF-κB in cancer cells. The dose of prodigiosin in those immunosuppression studies was usually low to nanomolar scale. Compared to those studies, the dose used in this study was relatively high for demonstrating the NF-κB inhibitory effect (Fig. 9, Fig. 15). This different dose re-quired for NF-κB inhibitoin could be resulted from the differences in cell type since the inhibitory concentrations 50 (IC₅₀) of MTT and MTS are consisted with other published results. Moreover, our results demonstrated that prodigiosin blocks the phosphorylation of IκBα, resulting in the inactivation of NF-κB signaling pathway (Fig. 4, Fig. 9, and Fig. 15). In addition, the EMSA data suggested that prodigiosin specifically inhibited the classical NF-κB signaling pathway. All these characteristics suggested that prodigiosin might be an IKKβ inhibitor.

4.4. Prodigiosin in combination with bortezomib exert synergistic cell toxicity in human multiple myeloma cells

Current chemotherapy seldom uses one drug alone. In most cases, doctor usually gives two or three chemodrugs for combination since most of cancers display drug resistance after a period of time. In this study, we demonstrated that prodigiosin is an effective agent as a chemotherapy candidate in multiple myeloma. In fact, our results suggested that prodigiosin induces growth inhibition and apoptosis in several other cancer types, including small cell lung cancer (SCLC) and none-small cell lung can-cer (NSCLC) (data not shown). Nevertheless, the TNFα induction system did not

work well in both of SCLC and NSCLC cell lines. Thus, we were unable to determine whether prodigiosin is an NF-κB inhibitor in the lung cancer cell line studies. The 26S proteasome inhibitor bortezomib, has exhibited good curative effect on multiple mye-loma. However, there were cases reported that some patients were resistance to bortezomib due to activation of the NF-κB pathway (Markovina, Callander et al.

2010). Additionally, the research suggested that bortezomib-induced apoptosis is not related to the repression of NF-κB activity. On the contrary, the studies revealed that bortezomib would activate NF-κB through classical pathway (Hideshima, Ikeda et al.

2009). The same group reported that an IKKβ inhibitor in combination with bortezomib overcame bortezomib resistance (Hideshima, Ikeda et al. 2009). In this thesis study, we demonstrated that prodigiosin suppressed the NF-κB activity induced by bortezomib in a human multiple myeloma cell line. This result supports our hy-pothesis that prodigiosin might be an IKKβ inhibitor.

For chemotherapy, doxorubicin is a common drug used in many types of cancers, including bladder, breast, lung, and multiple myeloma. It interacts with DNA by in-tercalation and inhibition of molecular biosynthesis; thus, it usually accompanies cardiotoxicity in higher dosage. Therefore, a combination with other chemodrugs is a good solution to reduce the dosage of doxorubicin. Our data showed that prodigiosin in combination with doxorubicin were not effective in treating multiple myeloma cells.

On the other hand, doxorubicin in combination with histone deacetylase inhibitor dis-played a synergistic effect (Sanchez, Shen et al. 2011).

Reference

Adachi, O., Kawai, T., Takeda, K., Matsumoto, M., Tsutsui, H., Sakagami, M., Nakanishi, K., and Akira, S. (1998). Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9, 143-150.

Aggarwal, B. B. (2003). Signalling pathways of the TNF superfamily: a double-edged sword. Nature reviews Immunology 3, 745-756.

Aggarwal, B. B., and Gehlot, P. (2009). Inflammation and cancer: how friendly is the relationship for cancer patients? Current opinion in pharmacology 9, 351-369.

Aggarwal, B. B., Vijayalekshmi, R. V., and Sung, B. (2009). Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe.

Clinical cancer research : an official journal of the American Association for Cancer Research 15, 425-430.

Ahn, K. S., Sethi, G., and Aggarwal, B. B. (2007). Nuclear factor-kappa B: from clone to clinic. Current molecular medicine 7, 619-637.

Amado, N. G., Fonseca, B. F., Cerqueira, D. M., Neto, V. M., and Abreu, J. G. (2011).

Flavonoids: potential Wnt/beta-catenin signaling modulators in cancer. Life sciences 89, 545-554.

Anand, P., Kunnumakkara, A. B., Sundaram, C., Harikumar, K. B., Tharakan, S. T., Lai, O. S., Sung, B., and Aggarwal, B. B. (2008). Cancer is a preventable disease that requires major lifestyle changes. Pharmaceutical research 25, 2097-2116.

Annunziata, C. M., Davis, R. E., Demchenko, Y., Bellamy, W., Gabrea, A., Zhan, F., Lenz, G., Hanamura, I., Wright, G., Xiao, W., et al. (2007). Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer cell 12, 115-130.

Basseres, D. S., and Baldwin, A. S. (2006). Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression. Oncogene 25, 6817-6830.

Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S., and Baltimore, D. (1995).

Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376, 167-170.

Bonizzi, G., and Karin, M. (2004). The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends in immunology 25, 280-288.

Cheng, G., and Xie, L. (2011). Parthenolide induces apoptosis and cell cycle arrest of

human 5637 bladder cancer cells in vitro. Molecules 16, 6758-6768.

Coussens, L. M., and Werb, Z. (2001). Inflammatory cells and cancer: think different!

The Journal of experimental medicine 193, F23-26.

D'Incalci, M., and Galmarini, C. M. (2010). A review of trabectedin (ET-743): a unique mechanism of action. Molecular cancer therapeutics 9, 2157-2163.

Dejardin, E., Droin, N. M., Delhase, M., Haas, E., Cao, Y., Makris, C., Li, Z. W., Karin, M., Ware, C. F., and Green, D. R. (2002). The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways.

Immunity 17, 525-535.

Dobrzanski, P., Ryseck, R. P., and Bravo, R. (1994). Differential interactions of Rel-NF-kappa B complexes with I kappa B alpha determine pools of constitutive and inducible NF-kappa B activity. The EMBO journal 13, 4608-4616.

Dolgin, E. (2011). Stem cells: Transplants on trial. Nature 480, S46-47.

Ghosh, S., and Karin, M. (2002). Missing pieces in the NF-kappaB puzzle. Cell 109 Suppl, S81-96.

Ghosh, S., May, M. J., and Kopp, E. B. (1998). NF-kappa B and Rel proteins:

evolutionarily conserved mediators of immune responses. Annual review of immunology 16, 225-260.

Glaser, K. B. (2007). HDAC inhibitors: clinical update and mechanism-based potential. Biochemical pharmacology 74, 659-671.

Gordaliza, M. (2007). Natural products as leads to anticancer drugs. Clinical &

translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 9, 767-776.

Guzman, E. A., Johnson, J. D., Linley, P. A., Gunasekera, S. E., and Wright, A. E.

(2011). A novel activity from an old compound: Manzamine A reduces the metastatic potential of AsPC-1 pancreatic cancer cells and sensitizes them to TRAIL-induced apoptosis. Investigational new drugs 29, 777-785.

Han, S. B., Kim, H. M., Kim, Y. H., Lee, C. W., Jang, E. S., Son, K. H., Kim, S. U., and Kim, Y. K. (1998). T-cell specific immunosuppression by prodigiosin isolated from Serratia marcescens. International journal of immunopharmacology 20, 1-13.

Hatada, E. N., Nieters, A., Wulczyn, F. G., Naumann, M., Meyer, R., Nucifora, G., McKeithan, T. W., and Scheidereit, C. (1992). The ankyrin repeat domains of the NF-kappa B precursor p105 and the protooncogene bcl-3 act as specific inhibitors

of NF-kappa B DNA binding. Proceedings of the National Academy of Sciences of the United States of America 89, 2489-2493.

Hayden, M. S., and Ghosh, S. (2004). Signaling to NF-kappaB. Genes & development 18, 2195-2224.

Hehner, S. P., Hofmann, T. G., Droge, W., and Schmitz, M. L. (1999). The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the I kappa B kinase complex. J Immunol 163, 5617-5623.

Heider, U., Hofbauer, L. C., Zavrski, I., Kaiser, M., Jakob, C., and Sezer, O. (2005).

Novel aspects of osteoclast activation and osteoblast inhibition in myeloma bone disease. Biochemical and biophysical research communications 338, 687-693.

Hideshima, T., Ikeda, H., Chauhan, D., Okawa, Y., Raje, N., Podar, K., Mitsiades, C., Munshi, N. C., Richardson, P. G., Carrasco, R. D., and Anderson, K. C. (2009).

Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood 114, 1046-1052.

Hideshima, T., Mitsiades, C., Tonon, G., Richardson, P. G., and Anderson, K. C.

(2007). Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nature reviews Cancer 7, 585-598.

Hideshima, T., Neri, P., Tassone, P., Yasui, H., Ishitsuka, K., Raje, N., Chauhan, D., NF-kappaB/Rel transcription factors defines functional specificities. The EMBO journal 22, 5530-5539.

Hoffmann, A., Levchenko, A., Scott, M. L., and Baltimore, D. (2002). The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. Science 298, 1241-1245.

Hsieh, H. Y., Shieh, J. J., Chen, C. J., Pan, M. Y., Yang, S. Y., Lin, S. C., Chang, J. S., Lee, A. Y., and Chang, C. C. (2012). Prodigiosin down-regulates SKP2 to induce p27(KIP1) stabilization and antiproliferation in human lung adenocarcinoma cells.

British journal of pharmacology 166, 2095-2108.

Huang, T. T., Kudo, N., Yoshida, M., and Miyamoto, S. (2000). A nuclear export

signal in the N-terminal regulatory domain of IkappaBalpha controls cytoplasmic localization of inactive NF-kappaB/IkappaBalpha complexes. Proceedings of the National Academy of Sciences of the United States of America 97, 1014-1019.

Huh, J. E., Yim, J. H., Lee, H. K., Moon, E. Y., Rhee, D. K., and Pyo, S. (2007).

Prodigiosin isolated from Hahella chejuensis suppresses lipopolysaccharide-induced NO production by inhibiting p38 MAPK, JNK and NF-kappaB activation in murine peritoneal macrophages. International immunopharmacology 7, 1825-1833.

Huynh, Q. K., Boddupalli, H., Rouw, S. A., Koboldt, C. M., Hall, T., Sommers, C., Hauser, S. D., Pierce, J. L., Combs, R. G., Reitz, B. A., et al. (2000).

Characterization of the recombinant IKK1/IKK2 heterodimer. Mechanisms regulating kinase activity. The Journal of biological chemistry 275, 25883-25891.

Hwang, I., Choi, Y. S., Jeon, M. Y., and Jeong, S. (2010). NF-kappaB p65 represses beta-catenin-activated transcription of cyclin D1. Biochemical and biophysical research communications 403, 79-84.

Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., and Thun, M. J. (2007). Cancer statistics, 2007. CA: a cancer journal for clinicians 57, 43-66.

Johnson, C., Van Antwerp, D., and Hope, T. J. (1999). An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IkappaBalpha. The EMBO journal 18, 6682-6693.

Jung, H. J., Chen, Z., Fayad, L., Wang, M., Romaguera, J., Kwak, L. W., and McCarty, N. (2012). Bortezomib-resistant nuclear factor kappaB expression in stem-like cells in mantle cell lymphoma. Experimental hematology 40, 107-118 e102.

Karin, M., and Ben-Neriah, Y. (2000). Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annual review of immunology 18, 621-663.

Kawai, T., Adachi, O., Ogawa, T., Takeda, K., and Akira, S. (1999). Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115-122.

Keats, J. J., Fonseca, R., Chesi, M., Schop, R., Baker, A., Chng, W. J., Van Wier, S., Tiedemann, R., Shi, C. X., Sebag, M., et al. (2007). Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer cell 12, 131-144.

Khoshnan, A., Bae, D., Tindell, C. A., and Nel, A. E. (2000). The physical association of protein kinase C theta with a lipid raft-associated inhibitor of kappa B factor

kinase (IKK) complex plays a role in the activation of the NF-kappa B cascade by TCR and CD28. J Immunol 165, 6933-6940.

Klement, J. F., Rice, N. R., Car, B. D., Abbondanzo, S. J., Powers, G. D., Bhatt, P. H., Chen, C. H., Rosen, C. A., and Stewart, C. L. (1996). IkappaBalpha deficiency results in a sustained NF-kappaB response and severe widespread dermatitis in mice. Molecular and cellular biology 16, 2341-2349.

Lee, J. S., Kim, Y. S., Park, S., Kim, J., Kang, S. J., Lee, M. H., Ryu, S., Choi, J. M., Oh, T. K., and Yoon, J. H. (2011). Exceptional production of both prodigiosin and cycloprodigiosin as major metabolic constituents by a novel marine bacterium, Zooshikella rubidus S1-1. Applied and environmental microbiology 77, 4967-4973.

Lernbecher, T., Kistler, B., and Wirth, T. (1994). Two distinct mechanisms contribute to the constitutive activation of RelB in lymphoid cells. The EMBO journal 13, 4060-4069.

Li, C. J., Guo, S. F., and Shi, T. M. (2012). Culture supernatants of breast cancer cell line MDA-MB-231 treated with parthenolide inhibit the proliferation, migration, and lumen formation capacity of human umbilical vein endothelial cells. Chinese medical journal 125, 2195-2199.

Li, Q., Van Antwerp, D., Mercurio, F., Lee, K. F., and Verma, I. M. (1999a). Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 284, 321-325.

Li, Z. W., Chu, W., Hu, Y., Delhase, M., Deerinck, T., Ellisman, M., Johnson, R., and Karin, M. (1999b). The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. The Journal of experimental medicine 189, 1839-1845.

Liang, M. C., Bardhan, S., Li, C., Pace, E. A., Porco, J. A., Jr., and Gilmore, T. D.

(2003). Jesterone dimer, a synthetic derivative of the fungal metabolite jesterone, blocks activation of transcription factor nuclear factor kappaB by inhibiting the inhibitor of kappaB kinase. Molecular pharmacology 64, 123-131.

Liang, M. C., Bardhan, S., Pace, E. A., Rosman, D., Beutler, J. A., Porco, J. A., Jr., and Gilmore, T. D. (2006). Inhibition of transcription factor NF-kappaB signaling proteins IKKbeta and p65 through specific cysteine residues by epoxyquinone A monomer: correlation with its anti-cancer cell growth activity. Biochemical

pharmacology 71, 634-645.

Lichstein, H. C., and Van De Sand, V. F. (1946). The Antibiotic Activity of Violacein, Prodigiosin, and Phthiocol. Journal of bacteriology 52, 145-146.

Llagostera, E., Soto-Cerrato, V., Montaner, B., and Perez-Tomas, R. (2003).

Prodigiosin induces apoptosis by acting on mitochondria in human lung cancer cells. Annals of the New York Academy of Sciences 1010, 178-181.

Los, M., Roodhart, J. M., and Voest, E. E. (2007). Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. The oncologist 12, 443-450.

Magae, J., Yamashita, M., and Nagai, K. (1993). Suppression of alloantigen presentation by prodigiosin, a T cell-specific immunosuppressant. Annals of the New York Academy of Sciences 685, 339-340.

Malek, S., Chen, Y., Huxford, T., and Ghosh, G. (2001). IkappaBbeta, but not IkappaBalpha, functions as a classical cytoplasmic inhibitor of NF-kappaB dimers by masking both NF-kappaB nuclear localization sequences in resting cells. The Journal of biological chemistry 276, 45225-45235.

Malek, S., Huang, D. B., Huxford, T., Ghosh, S., and Ghosh, G. (2003). X-ray crystal structure of an IkappaBbeta x NF-kappaB p65 homodimer complex. The Journal of biological chemistry 278, 23094-23100.

Markovina, S., Callander, N. S., O'Connor, S. L., Kim, J., Werndli, J. E., Raschko, M., Leith, C. P., Kahl, B. S., Kim, K., and Miyamoto, S. (2008). Bortezomib-resistant nuclear factor-kappaB activity in multiple myeloma cells. Molecular cancer research : MCR 6, 1356-1364.

Markovina, S., Callander, N. S., O'Connor, S. L., Xu, G., Shi, Y., Leith, C. P., Kim, K., Trivedi, P., Kim, J., Hematti, P., and Miyamoto, S. (2010). Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-kappaB activity in myeloma cells. Molecular cancer 9, 176.

Meier, P., Finch, A., and Evan, G. (2000). Apoptosis in development. Nature 407, 796-801.

Messori, A., Maratea, D., Nozzoli, C., and Bosi, A. (2011). The role of bortezomib, thalidomide and lenalidomide in the management of multiple myeloma: an overview of clinical and economic information. PharmacoEconomics 29, 269-285.

Michels, J., Johnson, P. W., and Packham, G. (2005). Mcl-1. The international journal

of biochemistry & cell biology 37, 267-271.

Mimeault, M., Johansson, S. L., and Batra, S. K. (2012). Pathobiological implications of the expression of EGFR, pAkt, NF-kappaB and MIC-1 in prostate cancer stem cells and their progenies. PloS one 7, e31919.

Montaner, B., Castillo-Avila, W., Martinell, M., Ollinger, R., Aymami, J., Giralt, E., and Perez-Tomas, R. (2005). DNA interaction and dual topoisomerase I and II inhibition properties of the anti-tumor drug prodigiosin. Toxicological sciences : an official journal of the Society of Toxicology 85, 870-879.

Montaner, B., and Perez-Tomas, R. (2001). Prodigiosin-induced apoptosis in human colon cancer cells. Life sciences 68, 2025-2036.

Montaner, B., and Perez-Tomas, R. (2002). Prodigiosin induces caspase-9 and caspase-8 activation and cytochrome C release in Jurkat T cells. Annals of the New York Academy of Sciences 973, 246-249.

Moreaux, J., Veyrune, J. L., De Vos, J., and Klein, B. (2009). APRIL is overexpressed in cancer: link with tumor progression. BMC cancer 9, 83.

Mortellaro, A., Songia, S., Gnocchi, P., Ferrari, M., Fornasiero, C., D'Alessio, R., Isetta, A., Colotta, F., and Golay, J. (1999). New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF-kappa B and AP-1 activation. J Immunol 162, 7102-7109.

Mukherjee, A. K., Basu, S., Sarkar, N., and Ghosh, A. C. (2001). Advances in cancer therapy with plant based natural products. Current medicinal chemistry 8, 1467-1486.

Nakamura, A., Nagai, K., Ando, K., and Tamura, G. (1986). Selective suppression by prodigiosin of the mitogenic response of murine splenocytes. The Journal of antibiotics 39, 1155-1159.

Nakano, H., Sakon, S., Koseki, H., Takemori, T., Tada, K., Matsumoto, M., Munechika, E., Sakai, T., Shirasawa, T., Akiba, H., et al. (1999). Targeted disruption of Traf5 gene causes defects in CD40- and CD27-mediated lymphocyte activation. Proceedings of the National Academy of Sciences of the United States of America 96, 9803-9808.

Newman, D. J., and Cragg, G. M. (2007). Natural products as sources of new drugs over the last 25 years. Journal of natural products 70, 461-477.

Noma, N., Simizu, S., Kambayashi, Y., Kabe, Y., Suematsu, M., and Umezawa, K.

(2012). Involvement of NF-kappaB-mediated expression of galectin-3-binding protein in TNF-alpha-induced breast cancer cell adhesion. Oncology reports 27, 2080-2084.

Oh, H., Jensen, P. R., Murphy, B. T., Fiorilla, C., Sullivan, J. F., Ramsey, T., and Fenical, W. (2010). Cryptosphaerolide, a cytotoxic Mcl-1 inhibitor from a marine-derived ascomycete related to the genus Cryptosphaeria. Journal of natural products 73, 998-1001.

Rao, P., Hayden, M. S., Long, M., Scott, M. L., West, A. P., Zhang, D., Oeckinghaus, A., Lynch, C., Hoffmann, A., Baltimore, D., and Ghosh, S. (2010). IkappaBbeta acts to inhibit and activate gene expression during the inflammatory response.

Nature 466, 1115-1119.

Richardson, P. G., Laubach, J. P., Schlossman, R. L., Ghobrial, I. M., Redman, K. C., McKenney, M., Warren, D., Noonan, K., Lunde, L., Doss, D., et al. (2012). The potential benefits of participating in early-phase clinical trials in multiple myeloma:

long-term remission in a patient with relapsed multiple myeloma treated with 90 cycles of lenalidomide and bortezomib. European journal of haematology 88, 446-449.

Rodriguez-Berriguete, G., Fraile, B., Paniagua, R., Aller, P., and Royuela, M. (2012).

Expression of NF-kappaB-related proteins and their modulation during TNF-alpha-provoked apoptosis in prostate cancer cells. The Prostate 72, 40-50.

Roodman, G. D. (2009). Pathogenesis of myeloma bone disease. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, UK 23, 435-441.

Ruland, J., and Mak, T. W. (2003). Transducing signals from antigen receptors to nuclear factor kappaB. Immunological reviews 193, 93-100.

Ryseck, R. P., Bull, P., Takamiya, M., Bours, V., Siebenlist, U., Dobrzanski, P., and Bravo, R. (1992). RelB, a new Rel family transcription activator that can interact with p50-NF-kappa B. Molecular and cellular biology 12, 674-684.

Sanchez, E., Shen, J., Steinberg, J., Li, M., Wang, C., Bonavida, B., Chen, H., Li, Z.

W., and Berenson, J. R. (2011). The histone deacetylase inhibitor LBH589 enhances the anti-myeloma effects of chemotherapy in vitro and in vivo. Leukemia research 35, 373-379.

Satoh, M., Oguro, R., Yamanaka, C., Takada, K., Matsuura, Y., Akiba, T., Aotsuka, N.,

Tani, Y., and Wakita, H. (2011). Clinical assessment of bortezomib for multiple myeloma in comparison with thalidomide. Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 14, 78-89.

Schmidmaier, R., Baumann, P., Bumeder, I., Meinhardt, G., Straka, C., and Emmerich, B. (2007). First clinical experience with simvastatin to overcome drug resistance in refractory multiple myeloma. European journal of haematology 79, 240-243.

Schumacher, M., Kelkel, M., Dicato, M., and Diederich, M. (2011). A survey of marine natural compounds and their derivatives with anti-cancer activity reported in 2010. Molecules 16, 5629-5646.

Senftleben, U., Cao, Y., Xiao, G., Greten, F. R., Krahn, G., Bonizzi, G., Chen, Y., Hu, Y., Fong, A., Sun, S. C., and Karin, M. (2001a). Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 293, 1495-1499.

Senftleben, U., Li, Z. W., Baud, V., and Karin, M. (2001b). IKKbeta is essential for

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