Induction of G2/M arrest and apoptosis by sesquiterpene lactones in human melanoma cell lines

Sharon Rozenblat, Shlomo Grossman, Margalit Bergman, Hugo Gottlieb, Yigal Cohen, Sara Dovrat

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59 Scopus citations


Malignant melanoma is a highly aggressive tumor which frequently resists chemotherapy, therefore, the search for new agents for its treatment is of great importance. In this study, we purified the sesquiterpene lactones (SLs), Tomentosin and Inuviscolide from Inula viscosa (Compositae) leaves and studied their anti-cancer potency against human melanoma cell lines in order to develop new agents for melanoma treatment. SLs inhibited the proliferation of three human melanoma cell lines: SK-28, 624 mel and 1363 mel in a dose-dependent manner. We further investigated SLs mechanism of action using SK-28 as a representative cell line model. SLs caused cell-cycle arrest at G2/M, accompanied by the appearance of a sub-G0 fraction, indicative of apoptotic cell death. Induction of apoptosis was further confirmed by changes in membrane phospholipids, changes in mitochondrial membrane potential (ΔΨ) and by detection of Caspase-3 activity. Rapid inhibitory phosphorylation of Cdc2 (Thr14 and Tyr15) was seen early after treatment, followed by a later decrease in the expression level of both Cyclin b1 and Cdc2. Induction of p53 and p21waf1 proteins and phosphorylation of p53 at Ser15 were also detected early after treatment. The anti-apoptotic proteins, p65 subunit of nuclear factor κB (NF-κB), and Survivin were reduced in a dose-dependent manner. Taken together, these changes partially explain the ability of the SLs to induce G2/M arrest and apoptosis. Induction of apoptosis by Tomentosin and Inuviscolide in human aggressive melanoma cell lines has high pharmacological value and implies that SLs might be developed as new agents for melanoma treatment.

Original languageEnglish
Pages (from-to)369-382
Number of pages14
JournalBiochemical Pharmacology
Issue number2
StatePublished - 15 Jan 2008

Bibliographical note

Funding Information:
We thank the members of Prof. Shlomo Grossman's laboratory for the helpful discussions. We thank Uri Karo for his help with the flow cytometry, Lucy Varshavsky for her help in the work with HPLC, and Sharon Victor for editorial assistance. We thank Dr. Arthur Machlenkin (Hadassah-Hebrew University Hospital, Sharett Institute, Jerusalem, Israel) for his help in the discussion. This research was partly supported by the Vinograd Foundation.


  • Apoptosis
  • Chemoresistance
  • G/M arrest
  • Melanoma
  • Sequiterpene lactones


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