nach oben

Investigational New Drugs

Erschienen in:

01.10.2014 | PRECLINICAL STUDIES

Novel antitumour indole alkaloid, Jerantinine A, evokes potent G2/M cell cycle arrest targeting microtubules

verfasst von: Vijay J. Raja, Kuan-Hon Lim, Chee-Onn Leong, Toh-Seok Kam, Tracey D. Bradshaw

Erschienen in: Investigational New Drugs | Ausgabe 5/2014

Einloggen, um Zugang zu erhalten

Summary

Natural products play a pivotal role in the treatment of cancer; identification of compounds such as taxanes and the vinca alkaloids were seminal landmarks in natural product drug discovery. Jerantinine A, a novel Aspidosperma alkaloid isolated from plant species Tabernaemontana corymbosa, was previously reported to possess cytotoxic activity against vincristine-resistant nasopharyngeal carcinoma cells and is therefore an ideal candidate for biological investigation. Furthermore, Tabernaemontana corymbosa, has been placed in the endangered list of threatened species by the International Union for Conservation of Nature thus making it a priority to elucidate the biological activity of this alkaloid. Herein, we report detailed biological evaluation of jerantinine A on various human-derived carcinoma cell lines. Our preliminary screens showed that significant inhibition of cell growth and colony formation accompanied time- and dose-dependent induction of apoptosis in human cancer cell lines after treatment with jerantinine A. Dose-dependent accumulations of cleaved PARP and caspase 3 further confirmed apoptosis. Profound G2/M cell cycle arrest was observed 24 h after treatment in all cell lines. Characteristics of mitotic arrest including inhibition of tubulin polymerisation, microtubule disruption, aneuploidy, and cyclin B1 down-regulation were clearly observed. The potent anti-proliferative, pro-apoptotic, and tubulin-destabilising activities of jerantinine A warrant further development of this molecule as a potential chemotherapeutic agent.

Cragg GM, Newman DJ (2005) Biodiversity: a continuing source of novel drug leads. Pure Appl Chem 77(1):7–24. doi:10.1351/pac200577010007 CrossRef

Mann J (2002) Natural products in cancer chemotherapy: past, present and future. Nat Rev Cancer 2(2):143–148CrossRefPubMed

Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the past 25 years. J Nat Prod 70(3):461–477CrossRefPubMed

Newman DJ, Cragg GM, Sander K (2003) Natural products as sources of new drugs over the period of 1981–2002. J Nat Prod 66(7):1022–1037CrossRefPubMed

Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75(3):311–335. doi:10.1021/np200906s PubMedCentralCrossRefPubMed

Lam F, Bradshaw TD, Mao H, Roberts S, Pan Y, Wang S (2012) ZJU-6, a novel derivative of Erianin, shows potent anti-tubulin polymerisation and anti-angiogenic activities. Investig New Drugs 30(5):1899–1907. doi:10.1007/s10637-011-9755-9 CrossRef

Gascoigne KE, Taylor SS (2009) How do anti-mitotic drugs kill cancer cells? J Cell Sci 122(Pt 15):2579–2585. doi:10.1242/jcs.039719 CrossRefPubMed

Lobert S, Vulevic B, Correia JJ (1996) Interaction of vinca alkaloids with tubulin: a comparison of vinblastine, vincristine, and vinorelbine. Biochemistry 35:6806–6814CrossRefPubMed

Amon A (1999) The spindle checkpoint. Curr Opin Cell Biol 9:69–75

10.

Burke DJ (2000) Complexity in the spindle checkpoint. Curr Opin Cell Biol 10:26–31CrossRef

11.

Rudner AD, Murray AW (1996) The spindle assembly checkpoint. Curr Opin Cell Biol 8:773–780CrossRefPubMed

12.

Blajeski AL, Phan VA, Kottke TJ, Kaufmann SH (2002) G1 and G2 cell-cycle arrest following microtubule depolymerization in human breast cancer cells. J Clin Investig 110(1):91–99. doi:10.1172/jci200213275 PubMedCentralCrossRefPubMed

13.

Vermuelen K, Bockstaele DRV, Berneman ZN (2003) The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36:131–149CrossRef

14.

Ling YH, Consoli U, Tornos C, Andreeff M, Perez-Soler R (1998) Accumulation of cyclin B1, activation of cyclin B1-dependent kinase and induction of programmed cell death in human epidermoid carcinoma KB cells treated with taxol. Int J Cancer 75(6):925–932CrossRefPubMed

15.

Tu Y, Cheng S, Zhang S, Sun H, Xu Z (2013) Vincristine induces cell cycle arrest and apoptosis in SH-SY5Y human neuroblastoma cells. Int J Mol Med 31(1):113–119. doi:10.3892/ijmm.2012.1167 PubMed

16.

Lim K-H, Hiraku O, Komiyama K, Kam T-S (2008) Jerantinines A-G, cytotoxic aspidosperma alkaloids from tabernaemontana corymbosa. J Nat Prod 71:1591–1594CrossRefPubMed

17.

Bradshaw TD, Stone EL, Trapani V, Leong CO, Matthews CS, te Poele R, Stevens MF (2008) Mechanisms of acquired resistance to 2-(4-Amino-3-methylphenyl)benzothiazole in breast cancer cell lines. Breast Cancer Res Treat 110(1):57–68. doi:10.1007/s10549-007-9690-9 CrossRefPubMed

18.

Nicoletti I (1991) A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 132(2):272–279

19.

Lee JC, Timasheff SN (1977) In vitro reconstitution of calf brain microtubules: effects of solution variables. Biochemistry 16(8):1754–1764CrossRefPubMed

20.

Shelanski M, Gaskin F, Cantor C (1973) Microtubule assembly in the absence of added nucleotides. Proc Natl Acad Sci U S A 70(3):765–768PubMedCentralCrossRefPubMed

21.

Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefPubMed

22.

Chen R, Keating MJ, Gandhi V, Plunkett W (2005) Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood 106:2513–2519PubMedCentralCrossRefPubMed

23.

Collins HM, Abdelghany MK, Messmer M, Yue B, Deeves SE, Kindle KB, Mantelingu K, Aslam A, Winkler GS, Kundu TK, Heery DM (2013) Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells. BMC Cancer 13:37. doi:10.1186/1471-2407-13-37 PubMedCentralCrossRefPubMed

24.

Lazo JS, Tamura K, Vogt A, Jung J-K, Rodriguez S, Balachandran R, Day BW, Wipf P (2000) Antimitotic actions of a novel analog of the fungal metabolite palmarumycin CP1. J Pharmacol Exp Ther 296(2):364–371

25.

Yuan J, Yan R, Kramer A, Eckerdt F, Roller M, Kaufmann M, Strebhardt K (2004) Cyclin B1 depletion inhibits proliferation and induces apoptosis in human tumor cells. Oncogene 23(34):5843–5852. doi:10.1038/sj.onc.1207757 CrossRefPubMed

26.

Rowinsky EK (1997) The development and clinical utility of the taxane class of antimicrotubule chemotherapy agents. Annu Rev Med 48:353–374CrossRefPubMed

27.

Xiao H, Verdier-Pinard P, Fernandez-Fuentes N, Burd B, Angeletti R, Fiser A, Horwitz SB, Orr GA (2006) Insights into the mechanism of microtubule stabilization by taxol. Proc Natl Acad Sci U S A 103(27):10166–10173. doi:10.1073/pnas.0603704103 PubMedCentralCrossRefPubMed

28.

Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell. J (2000) Section 19.3: kinesin, dynein, and intracellular transport. In: Molecular cell biology. 4th edn. W. H. Freeman, New York

29.

Cooper GM (2000) Microtubules. In: The cell: a molecular approach. 2nd edn. Sinauer Associates, Boston University

30.

Frei R, Staedler D, Raja A, Franke R, Sasse F, Gerber-Lemaire S, Waser J (2013) Total synthesis and biological evaluation of jerantinine E. Angew Chem. doi:10.1002/anie.201305533

31.

Gonzalez-Cid M, Cuello MT, Larripa I (1999) Comparison of the aneugenic effect of vinorelbine and vincristine in cultures human lymphocytes. Mutagenesis 14(1):63–66CrossRefPubMed

32.

Miller BM, Adler ID (1989) Suspect spindle poisons: analysis of c-mitotic effects in mouse bone marrow cells. Mutagenesis 4:208–215CrossRefPubMed

33.

Chen Q, Zhang X, Jiang Q, Clarke PR, Zhang C (2008) Cyclin B1 is localized to unattached kinetochores and contributes to efficient microtubule attachment and proper chromosome alignment during mitosis. Cell Res 18(2):268–280. doi:10.1038/cr.2008.11 CrossRefPubMed

34.

Hsu MH, Liu CY, Lin CM, Chen YJ, Chen CJ, Lin YF, Huang LJ, Lee KH, Kuo SC (2012) 2-(3-methoxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (HKL-1) induces G2/M arrest and mitotic catastrophe in human leukemia HL-60 cells. Toxicol Appl Pharmacol 259(2):219–226. doi:10.1016/j.taap.2011.12.026 CrossRefPubMed

35.

Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4(4):253–265. doi:10.1038/nrc1317 CrossRefPubMed

36.

Hengartner M (2000) Biochemistry of apoptosis. Nature 407:770CrossRefPubMed

37.

Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391:43–50CrossRefPubMed

38.

Podar K, Gouill SL, Zhang J, Opferman JT, Zorn E, Tai YT, Hideshima T, Amiot M, Chauhan D, Harousseau JL, Anderson KC (2008) A pivotal role for Mcl-1 in Bortezomib-induced apoptosis. Oncogene 27(6):721–731. doi:10.1038/sj.onc.1210679 CrossRefPubMed

39.

Hu J, Dang N, Song T, Vanderkerken K (2011) Mcl-1 reduction due to caspase-dependent cleavage during endoplasmic reticulum stress-induced apoptosis. J Biol Chem 286(44):le24. doi:10.1074/jbc.L111.233502, author reply le25PubMedCentralCrossRefPubMed

40.

Wetzler M, Segal D (2011) Omacetaxine as an anticancer therapeutic: what is old is new again. Curr Pharm Des 17(1):59–64CrossRefPubMed

41.

Chen R, Guo L, Chen Y, Jiang Y, Wierda WG, Plunkett W (2011) Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia. Blood 117(1):156–164. doi:10.1182/blood-2010-01-262808 PubMedCentralCrossRefPubMed

42.

Zhu BK, Wang P, Zhang XD, Jiang CC, Chen LH, Avery-Kiejda KA, Watts R, Hersey P (2008) Activation of Jun N-terminal kinase is a mediator of vincristine-induced apoptosis of melanoma cells. Anti-Cancer Drugs 19(2):189–200. doi:10.1097/CAD.0b013e3282f3138a CrossRefPubMed

43.

Tan G, Heqing L, Jiangbo C, Ming J, Yanhong M, Xianghe L, Hong S, Li G (2002) Apoptosis induced by low-dose paclitaxel is associated with p53 upregulation in nasopharyngeal carcinoma cells. Int J Cancer 97:168–172CrossRefPubMed

44.

Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF (2001) Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 3:339–345CrossRefPubMed

45.

Cohen GM, Sun X-M, Snowden RT, Dinsdale D, Skilleter DN (1992) Key morphological features of apoptosis may occur in the absence of internucleosomal DNA fragmentation. Biochem J 286:331–334PubMedCentralCrossRefPubMed

46.

Jordan MA, Wendell K, Gardiner S, Derry WB, Copp H, Wilson L (1996) Mitotic block induced in HeLa cells by low concentrations of paclitaxel (taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Res 56(4):816–825PubMed

47.

Eitaki M, Yamamori T, Meike S, Yasui H, Inami O (2012) Vincristine enhances amoeboid-like motility via GEF-H1/RhoA/ROCK/Myosin light chain signaling in MKN45 cells. BMC Cancer 12(469):1–12

48.

Fadoka VA, Bratton DL, Frasch SC, Warner ML, Henson PM (1998) The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ 5(7):551–562CrossRef

Titel: Novel antitumour indole alkaloid, Jerantinine A, evokes potent G2/M cell cycle arrest targeting microtubules
verfasst von: Vijay J. Raja
Kuan-Hon Lim
Chee-Onn Leong
Toh-Seok Kam
Tracey D. Bradshaw
Publikationsdatum: 01.10.2014
Verlag: Springer US
Erschienen in: Investigational New Drugs / Ausgabe 5/2014
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-014-0126-1

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Novel antitumour indole alkaloid, Jerantinine A, evokes potent G2/M cell cycle arrest targeting microtubules

Summary

Neu im Fachgebiet Onkologie

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

15% bedauern gewählte Blasenkrebs-Therapie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Update Onkologie

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Summary

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2014

The use of everolimus to reverse tamoxifen resistance in men with metastatic breast cancer: a case report

A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors

Atypical reversible posterior leukoencephalopathy syndrome (RPLS) induced by cediranib in a patient with metastatic rectal cancer

PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines

Activity of the polyamine-vectorized anti-cancer drug F14512 against pediatric glioma and neuroblastoma cell lines.

A phase I study of decitabine with pegylated interferon α-2b in advanced melanoma: impact on DNA methylation and lymphocyte populations

Neu im Fachgebiet Onkologie

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

15% bedauern gewählte Blasenkrebs-Therapie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Update Onkologie