Journal of Microbiology and Biotechnology

  • 제20권2호
  • /
  • Pages.433-437
  • /
  • 2010
  • /
  • 1017-7825(pISSN)
  • /
  • 1738-8872(eISSN)
한국미생물·생명공학회 (The Korean Society for Microbiology and Biotechnology)
권호 표지
DOI QR코드

DOI QR Code

Cell Cycle Arrest and Cytochrome c-mediated Apoptotic Induction in A549 Human Lung Cancer Cells by MCS-C2, an Analog of Sangivamycin

  • Kang, Jeong-Hwa (Department of Medical Genetics, College of Medicine, Hanyang University) ;
  • Lee, Dong-Keun (Department of Biological Sciences, College of Science, Konkuk University) ;
  • Lee, Chul-Hoon (Department of Medical Genetics, College of Medicine, Hanyang University)
  • 발행 : 2010.02.28
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

In the course of screening for novel modulators of cell cycle progression and apoptosis as anticancer drug candidates, we generated an analog of sangivamycin, MCS-C2, which was elucidated as 4-amino-6-bromo-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide. In the present study, we evaluated the molecular mechanisms of MCSC2-induced cell cycle arrest and apoptosis in A549 human lung cancer cells. To investigate the effects of MCS-C2 on cell cycle progression in A549 cells, we measured the DNA content of A549 cells treated with $5\;{\mu}M$ MCS-C2 using flow cytometry. The analysis revealed an appreciable $G_2$ phase arrest in treated cells. This event was associated with significant upregulation of p53 and $p21^{Cip1}$. In addition, the TUNEL assay was used to examine apoptotic induction in treated cells, and the effects of MCS-C2 on the expression of apoptosis-associated proteins were examined by Western blot. Apoptotic induction in MCS-C2-treated A549 cells was associated with cytochrome c release from mitochondria, which in turn resulted in the activation of caspase-9 and -3 and the cleavage of poly(ADP-ribose) polymerase (PARP). Based on these results, we conclude that MCS-C2 is a candidate therapeutic agent for the treatment of human lung cancer via upregulation and activation of p53.

키워드

참고문헌

  1. Canman, C. E., D. Lim, K. A. Cimprich, Y. Taya, K. Tamai, K. Sakaguchi, E. Appella, M. B. Kastan, and J. D. Siliciano. 1998. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281: 1677-1679. https://doi.org/10.1126/science.281.5383.1677
  2. Harper, J. W., G. R. Adami, N. Wei, K. Keyomarsi, and S. J. Elledge. 1993. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75: 805-816. https://doi.org/10.1016/0092-8674(93)90499-G
  3. Kim, M. K., H. L. Oh, B. Y. Choi, H. Lim, Y. H. Cho, and C.-H. Lee. 2007. CR229, a novel derivative of beta-carbolin-1-one, induces cell cycle arrest and apoptosis in HeLa cells via p53 activation. Cancer Sci. 98: 1402-1407. https://doi.org/10.1111/j.1349-7006.2007.00552.x
  4. Kim, M. K., J. Min, B. Y. Choi, H. Lim, Y. H. Cho, and C.-H. Lee. 2007. Discovery of cyclin-dependent kinase inhibitor, CR229, using structure-based drug screening. J. Microbiol. Biotechnol. 17: 1712-1716.
  5. Kim, M. K., Y. H. Cho, J. M. Kim, M. W. Chun, S. K. Lee, Y. Lim, and C.-H. Lee. 2005. Induction of apoptosis in human leukemia cells by MCS-C2 via caspase-dependent Bid cleavage and cytochrome c release. Cancer Lett. 223: 239-247. https://doi.org/10.1016/j.canlet.2004.10.045
  6. Lazebnik, Y. A., S. H. Kaufmann, S. Desnoyers, G. G. Poirier, and W. C. Earnshaw. 1994. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371: 346-347. https://doi.org/10.1038/371346a0
  7. Lee, C.-H., H. Lim, S. Moon, C. Shin, S. Kim, B. J. Kim, and Y. Lim. 2007. Novel anticancer agent, benzyldihydroxyoctenone, isolated from Streptomyces sp. causes G1 cell cycle arrest and induces apoptosis of HeLa cells. Cancer Sci. 98: 795-802. https://doi.org/10.1111/j.1349-7006.2007.00473.x
  8. Massague, J. 2004. G1 cell-cycle control and cancer. Nature 432: 298-306. https://doi.org/10.1038/nature03094
  9. Mufson, R. A. 1997. The role of serine/threonine phosphorylation in hematopoietic cytokine receptor signal transduction. FASEB J. 11: 37-44.
  10. Nicholson, D. W., A. Ali, N. A. Thornberry, J. P. Vaillancourt, C. K. Ding, M. Gallant, et al. 1995. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376: 37-43. https://doi.org/10.1038/376037a0
  11. Oh, H. L., H. Lim, Y. Park, Y. Lim, H. C. Koh, Y. H. Cho, and C.-H. Lee. 2009. HY253, a novel compound isolated from Aralia continentalis, induces apoptosis via cytochrome cmediated instrinsic pathway in HeLa cells. Bioorg. Med. Chem. Lett. 19: 797-799. https://doi.org/10.1016/j.bmcl.2008.12.009
  12. Park, H. Y., M. K. Kim, S. I. Moon, Y. H. Cho, and C.-H. Lee. 2006. Cell cycle arrest and apoptotic induction in LNCaP cells by MCS-C2, novel cyclin-dependent kinase inhibitor, through p53/p21WAF1/CIP1 pathway. Cancer Sci. 97: 430-436. https://doi.org/10.1111/j.1349-7006.2006.00195.x
  13. Reed, J. C. and M. Pellecchia. 2005. Apoptosis-based therapies for hematologic malignancies. Blood 106: 408-418. https://doi.org/10.1182/blood-2004-07-2761
  14. Renau, T. E., C. Kennedy, R. G. Ptak, J. M. Breitenbach, J. C. Drach, and L. B. Townsend. 1996. Synthesis of non-nucleoside analogs of toyocamycin, sangivamycin, and thiosangivamycin: The effect of certain 4- and 4,6-substituents on the antiviral activity of pyrrolo[2,3-d]pyrimidines. J. Med. Chem. 39: 3470-3476. https://doi.org/10.1021/jm950835y
  15. Tewari, M., L. T. Quan, K. O'Rourke, S. Desnoyers, Z. Zeng, D. R. Beidler, G. G. Poirier, G. S. Salvesen, and V. M. Dixit. 1995. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 81: 801-809. https://doi.org/10.1016/0092-8674(95)90541-3
  16. Yang, J., X. Liu, K. Bhalla, C. N. Kim, A. M. Ibrado, J. Cai, T. I. Peng, D. P. Jones, and X. Wang. 1997. Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science 275: 1129-1132. https://doi.org/10.1126/science.275.5303.1129

피인용 문헌

  1. Benzyldihydroxyoctenone, a Novel Nonsteroidal Antiandrogen, Shows Differential Apoptotic Induction in Prostate Cancer Cells in Response to Their Androgen Responsiveness vol.21, pp.5, 2010, https://doi.org/10.4014/jmb.1102.02033
  2. The Adjuvant Effect of Sophy ${\beta}$-Glucan to the Antibody Response in Poultry Immunized by the Avian Influenza A H5N1 and H5N2 Vaccines vol.21, pp.4, 2010, https://doi.org/10.4014/jmb.1011.11024
  3. Anticancer activity and mechanism of juglone on human cervical carcinoma HeLa cells vol.90, pp.11, 2010, https://doi.org/10.1139/y2012-134
  4. HY251, a Novel Decahydrocyclopenta[a]indene Analog, Induces Apoptosis via tBid-Mediated Intrinsic Pathway in Human Ovarian Cancer PA-1 Cells vol.22, pp.11, 2010, https://doi.org/10.4014/jmb.1209.09022
  5. Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death vol.9, pp.1, 2010, https://doi.org/10.1038/s41598-019-53223-0