The Antileukemic and Anti-Prostatic Effect of Aeroplysinin-1 Is Mediated through ROS-Induced Apoptosis via NOX Activation and Inhibition of HIF-1a Activity

Shou-Ping Shih; Mei-Chin Lu; Mohamed El-Shazly; Yu-Hsuan Lin; Chun-Lin Chen; Steve Sheng-Fa Yu; Yi-Chang Liu

doi:10.3390/life12050687

The Antileukemic and Anti-Prostatic Effect of Aeroplysinin-1 Is Mediated through ROS-Induced Apoptosis via NOX Activation and Inhibition of HIF-1a Activity

Life (Basel). 2022 May 5;12(5):687. doi: 10.3390/life12050687.

Authors

Shou-Ping Shih^{1

2}, Mei-Chin Lu^{3

4}, Mohamed El-Shazly^{5

6}, Yu-Hsuan Lin³, Chun-Lin Chen^{2

7

8

9}, Steve Sheng-Fa Yu¹⁰, Yi-Chang Liu^{11

12

13}

Affiliations

¹ Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
² Doctoral Degree Program in Marine Biotechnology, Academia Sinica, Taipei 115, Taiwan.
³ Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944, Taiwan.
⁴ National Museum of Marine Biology & Aquarium, Pingtung 944, Taiwan.
⁵ Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity Street, Cairo 11566, Egypt.
⁶ Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
⁷ Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
⁸ Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
⁹ Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
¹⁰ Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
¹¹ Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
¹² Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
¹³ Cellular Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.

Abstract

Aeroplysinin-1 is a brominated isoxazoline alkaloid that has exhibited a potent antitumor cell effect in previous reports. We evaluated the cytotoxicity of aeroplysinin-1 against leukemia and prostate cancer cells in vitro. This marine alkaloid inhibited the cell proliferation of leukemia Molt-4, K562 cells, and prostate cancer cells Du145 and PC-3 with IC₅₀ values of 0.12 ± 0.002, 0.54 ± 0.085, 0.58 ± 0.109 and 0.33 ± 0.042 µM, respectively, as shown by the MTT assay. Furthermore, in the non-malignant cells, CCD966SK and NR8383, its IC₅₀ values were 1.54 ± 0.138 and 6.77 ± 0.190 μM, respectively. In a cell-free system, the thermal shift assay and Western blot assay verified the binding affinity of aeroplysinin-1 to Hsp90 and Topo IIα, which inhibited their activity. Flow cytometry analysis showed that the cytotoxic effect of aeroplysinin-1 is mediated through mitochondria-dependent apoptosis induced by reactive oxygen species (ROS). ROS interrupted the cellular oxidative balance by activating NOX and inhibiting HIF-1α and HO-1 expression. Pretreatment with N-acetylcysteine (NAC) reduced Apl-1-induced mitochondria-dependent apoptosis and preserved the expression of NOX, HO-1, and HIF-1a. Our findings indicated that aeroplysinin-1 targeted leukemia and prostate cancer cells through multiple pathways, suggesting its potential application as an anti-leukemia and prostate cancer drug lead.

Keywords: NADPH oxidases (NOXs); aeroplysinin-1 (Apl-1); apoptosis; heat shock protein 90 (HSP90); reactive oxygen species (ROS); topoisomerase.

Abstract

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