Sains Malaysiana 52(12)(2023): 3823-3840

http://doi.org/10.17576/jsm-2023-5212-15

Pyranocycloartobiloxanthone A Suppressed Metastasis Ovarian Cancer Cells via S Phase Cell Cycle Arrest and Apoptosis

(Piranosikloartobilozanton A Menindas Metastasis Sel Kanser Ovari melalui Hentian Kitaran Sel Fasa S dan Apoptosis)

MASHITOH ABD RAHMAN¹, NAJIHAH MOHD HASHIM^1,2,* & IDRIS ADEWALE AHMED³

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Malaya, 50603 Kuala Lumpur, Malaysia

²Centre for Natural Products Research and Drug Discovery (CENAR), Universiti Malaya, 50603 Kuala Lumpur, Malaysia

³Department of Biotechnology, Faculty of Applied Science, Lincoln University, Kelana Jaya 47301 Petaling Jaya, Selangor, Malaysia

Diserahkan: 14 April 2023/Diterima: 11 Disember 2023

Abstract

Ovarian cancer is a deadly disease with a poor prognosis, highlighting the urgent need for novel therapeutic alternatives. Pyranocycloartobiloxanthone A (PA), an exceptional xanthone compound has garnered attention due to its diverse medicinal properties. This study aimed to investigate the anticancer properties of PA on metastatic ovarian cancer SKOV-3 cells. Cytotoxicity was evaluated using an MTT assay, while apoptotic mechanisms were determined using AO/PI double staining, annexin V-fluorescein isothiocyanate, multiple cytotoxicity-3, reactive oxygen species (ROS) production, caspases, real-time PCR, western blot, human apoptosis protein profile array and cell cycle analysis. PA inhibited SKOV-3 cell proliferation in a time-dependent manner, with an IC₅₀ of 7.0 ± 0.5 µg/mL and a selectivity index of 13.2 after 72 h of treatment. PA induced apoptosis through the intrinsic apoptotic pathway and arrested the cell cycle at the S phase. PA stimulated ROS production and disrupted the mitochondrial membrane potential, releasing cytochrome c from mitochondria to the cytosol. Additionally, results from human apoptotic protein profile indicated that 21 proteins were upregulated while 22 proteins were downregulated, including Bcl-2, survivin, and HSP70. These findings suggest that PA has the potential as a lead molecule in the development of a chemotherapy drug for ovarian cancer. However, further research is necessary to evaluate the safety and efficacy of PA in preclinical and clinical settings.

Keywords: Apoptosis; Artocarpus obtusus; cell cycle; ovarian cancer; pyranocycloartobiloxanthone A

Abstrak

Kanser ovari adalah penyakit yang membawa maut dengan prognosis yang kurang baik, menunjukkan keperluan yang mendesak untuk terapi alternatif yang novel. Piranosikloartobilozanton A (PA), sebatian zanton yang luar biasa telah menarik perhatian kerana sifat perubatannya yang pelbagai. Penyelidikan ini bertujuan untuk mengkaji sifat antikanser PA ke atas sel kanser ovari metastatis SKOV-3. Sitotoksisiti dinilai menggunakan asai MTT, manakala mekanisme apoptosis ditentukan menggunakan pewarnaan berganda AO/PI, annexin V-fluoresein isotiosianat, pelbagai sitotoksisiti-3, pengeluaran spesies oksigen reaktif (ROS), caspases, masa nyata PCR, pemblotan western, profil protein apoptosis manusia dan analisis kitaran sel. PA merencat proliferasi sel SKOV-3 bergantung kepada masa dengan IC₅₀ 7.0 ± 0.5 µg/mL dan indeks selektiviti sebanyak 13.2 selepas 72 jam rawatan. PA aruhan apoptosis melalui laluan apoptosis intrinsik dan menahan kitaran sel pada fasa S. PA merangsang pengeluaran ROS dan mengganggu potensi membran mitokondria, melepaskan sitokrom c daripada mitokondria ke sitosol. Selain itu, hasil daripada profil protein apoptosis manusia menunjukkan bahawa pengawalaturan 21 protein telah meningkat manakala 22 protein telah menurun termasuk Bcl-2, survivin dan HSP70. Penemuan ini mencadangkan bahawa PA mempunyai potensi sebagai molekul utama dalam membangunkan dadah kemoterapi untuk kanser ovari. Walau bagaimanapun, kajian lanjut adalah perlu untuk menilai keselamatan dan keberkesanan PA dalam konteks praklinikal dan klinikal.

Kata kunci: Apoptosis; Artocarpus obtusus; kanser ovari; kitaran sel; piranosikloartobilozanton A

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*Pengarang untuk surat-menyurat; email: najihahmh@um.edu.my