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Synergistic anticancer activities of the plant-derived sesquiterpene lactones salograviolide A and iso-seco-tanapartholide

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Abstract

We have previously shown that the two sesquiterpene lactones, salograviolide A (Sal A) and iso-seco-tanapartholide (TNP), isolated from the Middle Eastern indigenous plants Centaurea ainetensis and Achillea falcata, respectively, possess selective antitumor properties. Here, we aimed to assess the anticancer effects of the separate compounds and their combination, study their potential to generate reactive oxygen species (ROS), and investigate their underlying antitumor mechanisms in human colon cancer cell lines. Cells were treated with Sal A and TNP alone or in combination, and cell viability, cell cycle profile, apoptosis, ROS generation and changes in protein expression were monitored. Sal A and TNP in combination caused 80 % decrease in HCT-116 and DLD-1 cell viability versus only 25 % reduction when the drugs were used separately. The antitumor mechanism involved triggering ROS-dependent apoptosis as well as disruption of the mitochondrial membrane potential. Further studies showed that apoptosis by the Sal A and TNP combination was caspase-independent and that ERK, JNK and p38 of the serine/threonine MAPKs signaling pathway were involved in the cell death mechanism. Taken together, our data suggest that the combination of Sal A and TNP may be of therapeutic interest against colon cancer.

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Abbreviations

Bax:

Bcl-2-associated X protein

Bcl-2:

B cell lymphoma 2

DTT:

Dithiothreitol

ERK:

Extracellular signal-related kinase

JNK:

c-Jun-NH2-terminal kinase

MAPK:

Mitogen activated protein kinase

NAC:

N-Acetyl cysteine

NF-κB:

Nuclear factor-kappaB

PI:

Propidium iodide

ROS:

Reactive oxygen species

SL:

Sesquiterpene lactone

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Acknowledgments

This work was supported by grants from UNISANTIS and the research was conducted under the direction of the Nature Conservation Center for Sustainable Futures (Ibsar) at the American University of Beirut, Lebanon. We would like to thank members of the Central Research Science Laboratory at the American University of Beirut, Lebanon for their technical assistance with the use of the flow cytometer.

Conflict of interest

The authors declare that they have no competing financial interests.

Author information

Authors and Affiliations

  1. Department of Biology, American University of Beirut, Riad El-Solh, Beirut, Lebanon

    Mohamed Salla, Isabelle Fakhoury & Hala Gali-Muhtasib

  2. Department of Chemistry, American University of Beirut, Riad El-Solh, Beirut, Lebanon

    Najat Saliba

  3. Department of Biochemistry and Molecular Genetics, American University of Beirut, Riad El-Solh, Beirut, Lebanon

    Nadine Darwiche

  4. Ibsar-Nature Conservation Center for Sustainable Futures, American University of Beirut, Riad El-Solh, Beirut, Lebanon

    Najat Saliba, Nadine Darwiche & Hala Gali-Muhtasib

Authors
  1. Mohamed Salla
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  2. Isabelle Fakhoury
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  3. Najat Saliba
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  4. Nadine Darwiche
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  5. Hala Gali-Muhtasib
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Corresponding author

Correspondence to Hala Gali-Muhtasib.

Additional information

M. Salla and I. Fakhoury contributed equally

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Salla, M., Fakhoury, I., Saliba, N. et al. Synergistic anticancer activities of the plant-derived sesquiterpene lactones salograviolide A and iso-seco-tanapartholide. J Nat Med 67, 468–479 (2013). https://doi.org/10.1007/s11418-012-0703-6

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  • DOI: https://doi.org/10.1007/s11418-012-0703-6

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