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Plagioneurin B, a potent isolated compound induces apoptotic signalling pathways and cell cycle arrest in ovarian cancer cells

Nordin N, Majid NA, Othman R, Omer FAA, Nasharuddin MNA, Hashim NM

Apoptosis, 2018 02;23(2):152-169.
PMID: 29430581 DOI: 10.1007/s10495-018-1447-x

Plagioneurin B belongs to acetogenin group has well-established class of compounds. Acetogenin group has attracted worldwide attention in the past few years due their biological abilities as inhibitors for several types of tumour cells. Plagioneurin B was isolated via conventional chromatography and tested for thorough mechanistic apoptosis activity on human ovarian cancer cells (CAOV-3). Its structure was also docked at several possible targets using Autodock tools software. Our findings showed that plagioneurin B successfully inhibits the growth of CAOV-3 cells at IC50 of 0.62 µM. The existence of apoptotic bodies, cell membrane blebbing and chromatin condensation indicated the hallmark of apoptosis. Increase of Annexin V-FITC bound to phosphatidylserine confirmed the apoptosis induction in the cells. The apoptosis event was triggered through the extrinsic and intrinsic pathways via activation of caspases 8 and 9, respectively. Stimulation of caspase 3 and the presence of DNA ladder suggested downstream apoptotic signalling were initiated. Further confirmation of apoptosis was conducted at the molecular levels where up-regulation in Bax, as well as down-regulation of Bcl-2, Hsp-70 and survivin were observed. Plagioneurin B was also seen to arrest CAOV-3 cells cycle at the G2/M phase. Docking simulation of plagioneurin B with CD95 demonstrated that the high binding affinity and hydrogen bonds formation may explain the capability of plagioneurin B to trigger apoptosis. This study is therefore importance in finding the effective compound that may offer an alternative drug for ovarian cancer treatment.
Beta-mangostin from Cratoxylum arborescens activates the intrinsic apoptosis pathway through reactive oxygen species with downregulation of the HSP70 gene in the HL60 cells associated with a G0/G1 cell-cycle arrest

Omer FAA, Hashim NBM, Ibrahim MY, Dehghan F, Yahayu M, Karimian H, et al.

Tumour Biol., 2017 Nov;39(11):1010428317731451.
PMID: 29110583 DOI: 10.1177/1010428317731451

Xanthones are phytochemical compounds found in a number of fruits and vegetables. Characteristically, they are noted to be made of diverse properties based on their biological, biochemical, and pharmacological actions. Accordingly, the apoptosis mechanisms induced by beta-mangostin, a xanthone compound isolated from Cratoxylum arborescens in the human promyelocytic leukemia cell line (HL60) in vitro, were examined in this study. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was done to estimate the cytotoxicity effect of β-mangostin on the HL60 cell line. Acridine orange/propidium iodide and Hoechst 33342 dyes and Annexin V tests were conducted to detect the apoptosis features. Caspase-3 and caspase-9 activities; reactive oxygen species; real-time polymerase chain reaction for Bcl-2, Bax, caspase-3, and caspase-9 Hsp70 genes; and western blot for p53, cytochrome c, and pro- and cleavage-caspase-3 and caspase-9 were assessed to examine the apoptosis mechanism. Cell-cycle analysis conducted revealed that β-mangostin inhibited the growth of HL60 at 58 µM in 24 h. The administration of β-mangostin with HL60 caused cell morphological changes related to apoptosis which increased the number of early and late apoptotic cells. The β-mangostin-catalyzed apoptosis action through caspase-3, caspase-7, and caspase-9 activation overproduced reactive oxygen species which downregulated the expression of antiapoptotic genes Bcl-2 and HSP70. Conversely, the expression of the apoptotic genes Bax, caspase-3, and caspase-9 were upregulated. Meanwhile, at the protein level, β-mangostin activated the formation of cleaved caspase-3 and caspase-9 and also upregulated the p53. β-mangostin arrested the cell cycle at the G0/G1 phase. Overall, the results for β-mangostin showed an antiproliferative effect in HL60 via stopping the cell cycle at the G0/G1 phase and prompted the intrinsic apoptosis pathway.
Fulltext Potential Antitumor Effect of α-Mangostin against Rat Mammary Gland Tumors Induced by LA7 Cells

Ibrahim MY, Hashim NM, Omer FAA, Abubakar MS, Mohammed HA, Salama SM, et al.

Int J Mol Sci, 2023 Jun 17;24(12).
PMID: 37373429 DOI: 10.3390/ijms241210283

In this study, the chemotherapeutic effect of α-mangostin (AM) was assessed in rats injected with LA7 cells. Rats received AM orally at 30 and 60 mg/kg twice a week for 4 weeks. Cancer biomarkers such as CEA and CA 15-3 were significantly lower in AM-treated rats. Histopathological evaluations showed that AM protects the rat mammary gland from the carcinogenic effects of LA7 cells. Interestingly, AM decreased lipid peroxidation and increased antioxidant enzymes when compared to the control. Immunohistochemistry results of the untreated rats showed abundant PCNA and fewer p53-positive cells than AM-treated rats. Using the TUNEL test, AM-treated animals had higher apoptotic cell numbers than those untreated. This report revealed that that AM lessened oxidative stress, suppressed proliferation, and minimized LA7-induced mammary carcinogenesis. Therefore, the current study suggests that AM has significant potential for breast cancer treatment.
Fulltext Beta-mangostin demonstrates apoptogenesis in murine leukaemia (WEHI-3) cells in vitro and in vivo

Omer FAA, Hashim NM, Ibrahim MY, Aldoubi AF, Hassandarvish P, Dehghan F, et al.

BMC Complement Altern Med, 2017 Jul 17;17(1):366.
PMID: 28716025 DOI: 10.1186/s12906-017-1867-0

BACKGROUND: Beta-mangostin (BM) is a xanthone-type of natural compound isolated from Cratoxylum arborescens. This study aimed to examine the apoptosis mechanisms induced by BM in a murine monomyelocytic cell line (WEHI-3) in vitro and in vivo.
METHODS: A WEHI-3 cell line was used to evaluate the cytotoxicity of BM by MTT. AO/PI and Hoechst 33342 dyes, Annexin V, multiparametric cytotoxicity 3 by high content screening (HCS); cell cycle tests were used to estimate the features of apoptosis and BM effects. Caspase 3 and 9 activities, ROS, western blot for Bcl2, and Bax were detected to study the mechanism of apoptosis. BALB/c mice injected with WEHI-3 cells were used to assess the apoptotic effect of BM in vivo.
RESULTS: BM suppressed the growth of WEHI-3 cells at an IC50value of 14 ± 3 μg/mL in 24 h. The ROS production was increased inside the cells in the treated doses. Both caspases (9 and 3) were activated in treating WEHI-3 cells at 24, 48 and 72 h. Different signs of apoptosis were detected, such as cell membrane blebbing, DNA segmentation and changes in the asymmetry of the cell membrane. Another action by which BM could inhibit WEHI-3 cells is to restrain the cell cycle at the G1/G0 phase. In the in vivo study, BM reduced the destructive effects of leukaemia on the spleen and liver by inducing apoptosis in leukaemic cells.
CONCLUSION: BM exerts anti-leukaemic properties in vitro and in vivo.