亮氨酰tRNA合成酶作为抗肿瘤的潜在靶点
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摘要
由于肿瘤类型的复杂性和多样性以及肿瘤对单一靶点药物的抗药性,目前化疗药物所针对的靶点远远不能满足肿瘤治疗的需要,因而急待开发针对新型抗肿瘤药物的靶点。我们在研究抗锥虫亮氨酰tRNA合成酶(tbLeuRS)抑制剂对人源细胞毒性的过程中,发现有些抑制剂对人源亮氨酰tRNA合成酶(hLeuRS, LARS)有明显抑制,并可以抑制人的肿瘤细胞生长。由此我们提出:人源亮氨酰tRNA合成酶作为抗肿瘤药物的新靶点是可能的,而针对人源亮氨酰tRNA合成酶的抑制剂也有可能成为新型抗肿瘤药物。本课题试图在分子、细胞和动物水平验证亮氨酰tRNA合成酶成为抗肿瘤靶点的可能性,并对抑制这一靶点的抗肿瘤分子机制作出初步推断。
研究结果表明,由于结构的相似性,部分根据锥虫亮氨酰tRNA合成酶模拟设计的抑制物可以抑制人的亮氨酰tRNA合成酶(hLeuRS),并由此抑制人源细胞的增殖。亮氨酰tRNA合成酶抑制物(hLRSI)对抑制肿瘤细胞增殖有一定的选择性而这种选择性可能是由于肿瘤细胞在一定条件下比非肿瘤细胞增殖速度快造成的。与抑制蛋白合成的放线菌酮作用机制不同,hLRSI可能通过激活依赖p53的p21信号传导通道促进细胞早期凋亡,并使细胞周期阻断在G0/G1期。动物实验表明,hLRSI对移植瘤有一定的抑制作用,而对动物毒性较小。
综上所述,我们初步证实了亮氨酰tRNA合成酶是一个抗肿瘤药物的潜在靶点。这为进一步研究并利用这一靶点设计、合成、筛选新型抗肿瘤药物打下了基础。
Cancer is a deadly human disease that has multiple molecular causes and various types of cell origins. In addition, cancer cells often develop resistance to single-target anti-cancer drugs. Therefore, new anti-cancer targets are constantly called for in order to develop new chemotherapy drugs. We have found that some trypanosoma Leucyl-tRNA-synthetase (tbLeuRS) inhibitors also inhibited the growth of human cancer cells by the inhibition of human Leucyl-tRNA synthetase (hLeuRS/LARS). We propose that hLeuRS is a potential anti-cancer target and the inhibitors of this enzyme may develop into a new line of chemotherapy drugs. This thesis will try to verify this hypothesis through the design of a series of molecular, cellular and animal model experiments. The possible molecular mechanism of cancer cell inhibition by hLeuRS inhibitors is also touched on.
This thesis shows that some compounds designed to inhibit tbLeuRS also inhibit hLeuRS in vitro, and hLeuRS inhibitors suppress tumor cell proliferation. The results also show hLeuRS inhibitor selectively inhibits cancer cells and this selectivity may reflect the preferred inhibition of fast growing cells, a common characteristic of cancer cells. Indeed, in a xenograft mouse model, hLeuRS inhibitor showed inhibition to tumor growth while had little sign of toxicity. Different from cyclohexmide, a general protein synthesis inhibitor, hLeuRS inhibitor activates p53 dependent p21 signaling pathway and promotes early apoptosis and G0/G1 cell cycle blocking.
Taken together, this thesis proposed and showed hLeuRS is a potential anticancer drug target. These results will warrant the further study of hLeuRS as an anti-cancer target for the development of new lines of anti-cancer drugs.
研究结果表明,由于结构的相似性,部分根据锥虫亮氨酰tRNA合成酶模拟设计的抑制物可以抑制人的亮氨酰tRNA合成酶(hLeuRS),并由此抑制人源细胞的增殖。亮氨酰tRNA合成酶抑制物(hLRSI)对抑制肿瘤细胞增殖有一定的选择性而这种选择性可能是由于肿瘤细胞在一定条件下比非肿瘤细胞增殖速度快造成的。与抑制蛋白合成的放线菌酮作用机制不同,hLRSI可能通过激活依赖p53的p21信号传导通道促进细胞早期凋亡,并使细胞周期阻断在G0/G1期。动物实验表明,hLRSI对移植瘤有一定的抑制作用,而对动物毒性较小。
综上所述,我们初步证实了亮氨酰tRNA合成酶是一个抗肿瘤药物的潜在靶点。这为进一步研究并利用这一靶点设计、合成、筛选新型抗肿瘤药物打下了基础。
Cancer is a deadly human disease that has multiple molecular causes and various types of cell origins. In addition, cancer cells often develop resistance to single-target anti-cancer drugs. Therefore, new anti-cancer targets are constantly called for in order to develop new chemotherapy drugs. We have found that some trypanosoma Leucyl-tRNA-synthetase (tbLeuRS) inhibitors also inhibited the growth of human cancer cells by the inhibition of human Leucyl-tRNA synthetase (hLeuRS/LARS). We propose that hLeuRS is a potential anti-cancer target and the inhibitors of this enzyme may develop into a new line of chemotherapy drugs. This thesis will try to verify this hypothesis through the design of a series of molecular, cellular and animal model experiments. The possible molecular mechanism of cancer cell inhibition by hLeuRS inhibitors is also touched on.
This thesis shows that some compounds designed to inhibit tbLeuRS also inhibit hLeuRS in vitro, and hLeuRS inhibitors suppress tumor cell proliferation. The results also show hLeuRS inhibitor selectively inhibits cancer cells and this selectivity may reflect the preferred inhibition of fast growing cells, a common characteristic of cancer cells. Indeed, in a xenograft mouse model, hLeuRS inhibitor showed inhibition to tumor growth while had little sign of toxicity. Different from cyclohexmide, a general protein synthesis inhibitor, hLeuRS inhibitor activates p53 dependent p21 signaling pathway and promotes early apoptosis and G0/G1 cell cycle blocking.
Taken together, this thesis proposed and showed hLeuRS is a potential anticancer drug target. These results will warrant the further study of hLeuRS as an anti-cancer target for the development of new lines of anti-cancer drugs.
引文
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3-kinase/Akt/mammalian target of rapamycin pathway. Clinical Cancer Research, 2006. 12(3): p.
679-689.
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29. Folkman, J., Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg, 1972. 175(3): p. 409-416.
30. Gerber, H.P. and N. Ferrara, Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res, 2005. 65(3): p. 671-680.
31. Hicklin, D. and L. Ellis, Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. Journal of Clinical Oncology, 2005. 23(5): p. 1011-1027.
32. Konerding, M., E. Fait, and A. Gaumann, 3D microvascular architecture of pre-cancerous lesions and invasive carcinomas of the colon. British journal of cancer, 2001. 84(10): p. 1354-1362.
33. Hinnen, P. and F. Eskens, Vascular disrupting agents in clinical development. British journal of cancer, 2007. 96(8): p. 1159-1165.
34. Ching, L., et al., Induction of endothelial cell apoptosis by the antivascular agent 5, 6-dimethylxanthenone-4-acetic acid. British journal of cancer, 2002. 86(12): p. 1937-1942.
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37. Stupp, R. and C. Ruegg, Integrin inhibitors reaching the clinic. Journal of Clinical Oncology, 2007. 25(13): p. 1637-1638.
38. Giannakakou, P., D. Sackett, and T. Fojo, Tubulin/microtubules: still a promising target for new chemotherapeutic agents. JNCI Journal of the National Cancer Institute, 2000. 92(3): p. 182-183.
39. Johnstone, R., Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nature reviews drug discovery, 2002. 1(4): p. 287-299.
40.高红军,氨基酸与肿瘤.肿瘤学杂志, 2002. 8(1) : p.1-3
41.刘权焰,不平衡氨基酸对肿瘤生长的影响.肠外与肠内营养, 2001. 8(2) : p.83-85
42. Medina, M., J. M¨￠rquez, and C. N¨2 ez, Interchange of amino acids between tumor and host. Biochemical medicine and metabolic biology, 1992. 48(1): p. 1-7.
43. Klimberg, V., et al., Effect of supplemental dietary glutamine on methotrexate concentrations in tumors. Archives of Surgery, 1992. 127(11): p. 1317-1320.
44. Marc Rhoads, J. and G. Wu, Glutamine, arginine, and leucine signaling in the intestine. Amino Acids, 2009. 37(1): p. 111-122.
45. Guertin, D. and D. Sabatini, Defining the role of mTOR in cancer. Cancer Cell, 2007. 12(1): p. 9-22.
46. Laplante, M. and D. Sabatini, mTOR signaling at a glance. Journal of Cell Science, 2009. 122(20): p. 3589-3594.
47. Nicklin, P., et al., Bidirectional transport of amino acids regulates mTOR and autophagy. Cell, 2009. 136(3): p. 521-534.
48. Thomas, H. and S. Kozma, Targeting mTOR Signaling Pathways in Liver Disease. Signaling Pathways in Liver Diseases, 2009: p. 261-273.
49. Barbet, N., et al., TOR controls translation initiation and early G1 progression in yeast. Molecular biology of the cell, 1996. 7(1): p. 25-42.
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2. Ma, W.W. and A.A. Adjei, Novel agents on the horizon for cancer therapy. CA Cancer J Clin, 2009. 59(2): p. 111-137.
3. Espinosa, E., et al., Classification of anticancer drugs--a new system based on therapeutic targets. Cancer Treatment Reviews, 2003. 29(6): p. 515-523.
4. Sawyers, C., Targeted cancer therapy. Nature, 2004. 432(7015): p. 294-297.
5.车文军,抗肿瘤药物新靶点与新药研究.药学进展, 2007. 31(6): p. 247-253
6. Hurley, L., DNA and its associated processes as targets for cancer therapy. Nature Reviews Cancer, 2002. 2(3): p. 188-200.
7. Weidmann, E., et al., Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin's lymphoma. Annals of oncology, 2002. 13(8): p. 1285-1289.
8. Calvert, H. and P. Bunn. Future directions in the development of pemetrexed. Seminars in oncology, 2002. 29(2): p. 54–61.
9.胡国清,译,恶性肿瘤的药物治疗.沈阳,辽宁科学出版社, 2001: p. 7-17.
10.陈振东,秦.,秦叔逵,肿瘤生物学概论.北京:人民军医出版社, 2006: p. 48-49.
11.林莉萍,丁.,针对分子靶点的抗肿瘤药物研究进展.中国新药杂志, 2006. 15(3): p. 167-174.
12. Tolcher, A. Preliminary phase I results of G3139 (bcl-2 antisense oligonucleotide) therapy in combination with docetaxel in hormone-refractory prostate cancer. Seminal in oncology, 2001. 28(4): p. 67–70.
13. Del Bufalo, D., et al., Effect of cisplatin and c-myc antisense phosphorothioate oligodeoxynucleotides combination on a human colon carcinoma cell line in vitro and in vivo. British journal of cancer, 1996. 74(3): p. 387-393.
14. Rieber, M., U. Zangemeister-Wittke, and M. Rieber, p53-independent induction of apoptosis in human melanoma cells by a bcl-2/bcl-xL bispecific antisense oligonucleotide. Clinical Cancer Research, 2001. 7(5): p. 1446-1451.
15. Jansen, B. and U. Zangemeister-Wittke, Antisense therapy for cancer--the time of truth. The Lancet Oncology, 2002. 3(11): p. 672-683.
16. Carpenter, G. and S. Cohen, Epidermal growth factor. Annual review of biochemistry, 1979. 48(1): p. 193-216.
17. Yarden, Y. and M. Sliwkowski, Untangling the ErbB signalling network. Nat Rev Mol Cell Biol, 2001. 2(2): p. 127-137.
18. Mendelsohn, J. and J. Baselga. Epidermal growth factor receptor targeting in cancer. Elsevier, 2006, 33(4): p. 369–385.
19. Birchmeier, C., et al., Met, metastasis, motility and more. Nature Reviews Molecular Cell Biology, 2003.4(12): p. 915-925.
20. Rosario, M. and W. Birchmeier, How to make tubes: signaling by the Met receptor tyrosine kinase. Trends in cell biology, 2003. 13(6): p. 328-335.
21. Sachdev, D. and D. Yee, Disrupting insulin-like growth factor signaling as a potential cancer therapy. Molecular cancer therapeutics, 2007. 6(1): p. 1-12.
22. Sciacca, L., et al., Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism. Oncogene(Basingstoke), 1999. 18(15): p. 2471-2479.
23. Pollak, M., Insulin-like growth factor-related signaling and cancer development. Recent Results in Cancer Research, 2007. 174: p. 49-53.
24.黄敏,抗肿瘤药物新靶点.中国处方药, 2006. (12): p. 10-15.
25. Katso, R., et al., Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol, 2001. 17: p. 615-75.
26. Granville, C., et al., Handicapping the race to develop inhibitors of the phosphoinositide
3-kinase/Akt/mammalian target of rapamycin pathway. Clinical Cancer Research, 2006. 12(3): p.
679-689.
27. Sebolt-Leopold, J. and R. Herrera, Targeting the mitogen-activated protein kinase cascade to treat cancer. Nature Reviews Cancer, 2004. 4(12): p. 937-947.
28. Sridhar, S., D. Hedley, and L. Siu, Raf kinase as a target for anticancer therapeutics. Molecular cancer therapeutics, 2005. 4(4): p. 677-685.
29. Folkman, J., Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg, 1972. 175(3): p. 409-416.
30. Gerber, H.P. and N. Ferrara, Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res, 2005. 65(3): p. 671-680.
31. Hicklin, D. and L. Ellis, Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. Journal of Clinical Oncology, 2005. 23(5): p. 1011-1027.
32. Konerding, M., E. Fait, and A. Gaumann, 3D microvascular architecture of pre-cancerous lesions and invasive carcinomas of the colon. British journal of cancer, 2001. 84(10): p. 1354-1362.
33. Hinnen, P. and F. Eskens, Vascular disrupting agents in clinical development. British journal of cancer, 2007. 96(8): p. 1159-1165.
34. Ching, L., et al., Induction of endothelial cell apoptosis by the antivascular agent 5, 6-dimethylxanthenone-4-acetic acid. British journal of cancer, 2002. 86(12): p. 1937-1942.
35.唐雪莲,李.,耿美玉,等,整合素与肿瘤转移.中国药理学通报, 2005. 21(10): p.1164-1167
36. Ramakrishnan, V., et al., Preclinical evaluation of an anti-alpha5beta1 integrin antibody as a novel anti-angiogenic agent. Journal of experimental therapeutics & oncology, 2006. 5(4): p. 273-286.
37. Stupp, R. and C. Ruegg, Integrin inhibitors reaching the clinic. Journal of Clinical Oncology, 2007. 25(13): p. 1637-1638.
38. Giannakakou, P., D. Sackett, and T. Fojo, Tubulin/microtubules: still a promising target for new chemotherapeutic agents. JNCI Journal of the National Cancer Institute, 2000. 92(3): p. 182-183.
39. Johnstone, R., Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nature reviews drug discovery, 2002. 1(4): p. 287-299.
40.高红军,氨基酸与肿瘤.肿瘤学杂志, 2002. 8(1) : p.1-3
41.刘权焰,不平衡氨基酸对肿瘤生长的影响.肠外与肠内营养, 2001. 8(2) : p.83-85
42. Medina, M., J. M¨￠rquez, and C. N¨2 ez, Interchange of amino acids between tumor and host. Biochemical medicine and metabolic biology, 1992. 48(1): p. 1-7.
43. Klimberg, V., et al., Effect of supplemental dietary glutamine on methotrexate concentrations in tumors. Archives of Surgery, 1992. 127(11): p. 1317-1320.
44. Marc Rhoads, J. and G. Wu, Glutamine, arginine, and leucine signaling in the intestine. Amino Acids, 2009. 37(1): p. 111-122.
45. Guertin, D. and D. Sabatini, Defining the role of mTOR in cancer. Cancer Cell, 2007. 12(1): p. 9-22.
46. Laplante, M. and D. Sabatini, mTOR signaling at a glance. Journal of Cell Science, 2009. 122(20): p. 3589-3594.
47. Nicklin, P., et al., Bidirectional transport of amino acids regulates mTOR and autophagy. Cell, 2009. 136(3): p. 521-534.
48. Thomas, H. and S. Kozma, Targeting mTOR Signaling Pathways in Liver Disease. Signaling Pathways in Liver Diseases, 2009: p. 261-273.
49. Barbet, N., et al., TOR controls translation initiation and early G1 progression in yeast. Molecular biology of the cell, 1996. 7(1): p. 25-42.
50. Proud, C., Role of mTOR signaling in the control of translation initiation and elongation by nutrients. Current topics in microbiology and immunology, 2003: p. 215-244.
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