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Mar. Drugs 2018, 16(1), 18; https://doi.org/10.3390/md16010018

Isoaaptamine Induces T-47D Cells Apoptosis and Autophagy via Oxidative Stress

1
Division of Surgical Oncology, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
2
Division of Urology, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 802, Taiwan
3
Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan
4
Division of Urology, Department of Surgery, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 813, Taiwan
5
Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity Street, Abassia, Cairo 115, Egypt
6
Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 114, Egypt
7
National Museum of Marine Biology & Aquarium, Pingtung 944, Taiwan
8
Graduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung 944, Taiwan
9
Department and Graduate Institute of Aquaculture, National Kaohsiung Marine University, Kaohsiung 811, Taiwan
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 6 December 2017 / Revised: 22 December 2017 / Accepted: 4 January 2018 / Published: 9 January 2018
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Abstract

Aaptos is a genus of marine sponge which belongs to Suberitidae and is distributed in tropical and subtropical oceans. Bioactivity-guided fractionation of Aaptos sp. methanolic extract resulted in the isolation of aaptamine, demethyloxyaaptamine, and isoaaptamine. The cytotoxic activity of the isolated compounds was evaluated revealing that isoaaptamine exhibited potent cytotoxic activity against breast cancer T-47D cells. In a concentration-dependent manner, isoaaptamine inhibited the growth of T-47D cells as indicated by short-(MTT) and long-term (colony formation) anti-proliferative assays. The cytotoxic effect of isoaaptamine was mediated through apoptosis as indicated by DNA ladder formation, caspase-7 activation, XIAP inhibition and PARP cleavage. Transmission electron microscopy and flow cytometric analysis using acridine orange dye indicated that isoaaptamine treatment could induce T-47D cells autophagy. Immunoblot assays demonstrated that isoaaptamine treatment significantly activated autophagy marker proteins such as type II LC-3. In addition, isoaaptamine treatment enhanced the activation of DNA damage (γH2AX) and ER stress-related proteins (IRE1 α and BiP). Moreover, the use of isoaaptamine resulted in a significant increase in the generation of reactive oxygen species (ROS) as well as in the disruption of mitochondrial membrane potential (MMP). The pretreatment of T-47D cells with an ROS scavenger, N-acetyl-l-cysteine (NAC), attenuated the apoptosis and MMP disruption induced by isoaaptamine up to 90%, and these effects were mediated by the disruption of nuclear factor erythroid 2-related factor 2 (Nrf 2)/p62 pathway. Taken together, these findings suggested that the cytotoxic effect of isoaaptamine is associated with the induction of apoptosis and autophagy through oxidative stress. Our data indicated that isoaaptamine represents an interesting drug lead in the war against breast cancer. View Full-Text
Keywords: anti-cancer; apoptosis; autophagy; isoaaptamine; Nrf2/p62; ROS anti-cancer; apoptosis; autophagy; isoaaptamine; Nrf2/p62; ROS
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Wu, C.-F.; Lee, M.-G.; El-Shazly, M.; Lai, K.-H.; Ke, S.-C.; Su, C.-W.; Shih, S.-P.; Sung, P.-J.; Hong, M.-C.; Wen, Z.-H.; Lu, M.-C. Isoaaptamine Induces T-47D Cells Apoptosis and Autophagy via Oxidative Stress. Mar. Drugs 2018, 16, 18.

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