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Mar. Drugs 2018, 16(6), 212; https://doi.org/10.3390/md16060212

Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin Expression

1
The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 404, Taiwan
2
Graduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung 944, Taiwan
3
National Museum of Marine Biology & Aquarium, Pingtung 944, Taiwan
4
Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity Street, Abassia, Cairo 11566, Egypt
5
Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11432, Egypt
6
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
7
Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
8
Department of Urology, Sinying Hospital, Ministry of Health and Welfare, Tainan 730, Taiwan
9
Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
10
Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 22 May 2018 / Revised: 14 June 2018 / Accepted: 15 June 2018 / Published: 17 June 2018
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Abstract

Heteronemin, the most abundant secondary metabolite in the sponge Hippospongia sp., exhibited potent cytotoxic activity against several cancer cell lines. It increased the percentage of apoptotic cells and reactive oxygen species (ROS) in Molt4 cells. The use of ROS scavenger, N-acetyl cysteine (NAC), suppressed both the production of ROS from mitochondria and cell apoptosis that were induced by heteronemin treatment. Heteronemin upregulated talin and phosphorylated talin expression in Molt4 cells but it only upregulated the expression of phosphorylated talin in HEK293 cells. However, pretreatment with NAC reversed these effects. Talin siRNA reversed the activation of pro-apoptotic cleaved caspases 3 and 9. On the other hand, the downstream proteins including FAK and NF-κB (p65) were not affected. In addition, we confirmed that heteronemin directly modulated phosphorylated talin expression through ROS generation resulting in cell apoptosis, but it did not affect talin/FAK complex. Furthermore, heteronemin interfered with actin microfilament and caused morphology changes. Taken together, these findings suggest that the cytotoxic effect of heteronemin is associated with oxidative stress and induction of phosphorylated talin expression. Our results suggest that heteronemin represents an interesting candidate which can be further developed as a drug lead against leukemia. View Full-Text
Keywords: heteronemin; reactive oxygen species; mitochondrial; talin; phosphorylated talin heteronemin; reactive oxygen species; mitochondrial; talin; phosphorylated talin
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Chen, Y.-C.; Lu, M.-C.; El-Shazly, M.; Lai, K.-H.; Wu, T.-Y.; Hsu, Y.-M.; Lee, Y.-L.; Liu, Y.-C. Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin Expression. Mar. Drugs 2018, 16, 212.

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