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Pharmaceutical Research

, Volume 21, Issue 12, pp 2307–2319 | Cite as

Marine Alkaloid Polycarpine and Its Synthetic Derivative Dimethylpolycarpine Induce Apoptosis in JB6 Cells Through p53- and Caspase 3-Dependent Pathways

  • Sergey N. Fedorov
  • Ann M. Bode
  • Valentin A. Stonik
  • Irina A. Gorshkova
  • Patricia C. Schmid
  • Oleg S. Radchenko
  • Evgueni V. Berdyshev
  • Zigang Dong
Article

No Heading

Purpose.

Polycarpine from ascidian Polycarpa aurata was previously found to be active against different human tumor cells. In this study, we investigated the antitumor mechanisms of polycarpine and its synthetic derivative, desmethoxyethoxy-polycarpine (dimethylpolycarpine), through the induction of apoptosis. This new knowledge regarding the proapoptotic action of polycarpine and dimethylpolycarpine should lead to a better understanding of their effects and development of a new class of anticancer drugs.

Methods.

Apoptosis was clearly observed by flow cytometry and Western blotting using an antibody against cleaved caspase-3 as an apoptotic marker.

Results.

Polycarpines differentially activated p38 kinase, JNKs, and ERKs in JB6 Cl 41 cells. The polycarpines-induced apoptosis was decreased in cells expressing a dominant-negative mutant of JNK. Both compounds stimulated p53-dependent transcriptional activity and phosphorylation. Induction of p53-phosphorylation at serine 15 was suppressed in JNK1 and JNK2 knockout cells. Furthermore, polycarpines were unable to induce apoptosis in p53-deficient MEFs in contrast to a strong induction of apoptosis in wild type MEFs, suggesting that p53 is involved in apoptosis induced by polycarpines. The p53 phosphorylation in turn was mediated by activated JNKs.

Conclusions.

These results indicate that all three MAPK signaling pathways are involved in the response of JB6 cells to treatment with polycarpines. Evidence also supports a proapoptotic role of the JNKs signaling pathway in vivo and clearly indicates that JNKs are required for phosphorylation of c-Jun, activation of p53, and subsequent apoptosis induced by polycarpines.

Key words:

nanticancer action apoptosis marine 

Abbreviations

EGF

epidermal growth factor

ERKs

extracellular signal-regulated protein kinases

FBS

fetal bovine serum

JNKs

c-Jun NH2-terminal kinases

MAPKs

mitogen-activated protein kinases

MEM

minimum essential medium

PAGE

polyacrylamide gel electrophoresis

polycarpine

bis[2-amino-4-(4-methoxyphenyl)-1-methyl-5-imidazolyl]disulfide dihydrochloride TPA, 12-O-tetradecanoyl-phorbol-13-acetate

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Copyright information

© Springer Science+Business Media, Inc. 2004

Authors and Affiliations

  • Sergey N. Fedorov
    • 1
  • Ann M. Bode
    • 1
  • Valentin A. Stonik
    • 2
  • Irina A. Gorshkova
    • 2
  • Patricia C. Schmid
    • 1
  • Oleg S. Radchenko
    • 2
  • Evgueni V. Berdyshev
    • 3
  • Zigang Dong
    • 1
    • 3
  1. 1.Hormel InstituteUniversity of MinnesotaAustinUSA
  2. 2.Pacific Institute of Bioorganic ChemistryVladivostokRussia
  3. 3.Division of Pulmonary and Critical Care MedicineJohns Hopkins University, Asthma and Allergy CenterBaltimoreUSA

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