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Liriodenine, an aporphine alkaloid from Enicosanthellum pulchrum, inhibits proliferation of human ovarian cancer cells through induction of apoptosis via the mitochondrial signaling pathway and blocking cell cycle progression.

Nordin N, Majid NA, Hashim NM, Rahman MA, Hassan Z, Ali HM - Drug Des Devel Ther (2015)

Bottom Line: The result showed that liriodenine inhibits proliferation of CAOV-3 cells at 37.3 μM after 24 hours of exposure.Involvement of the intrinsic pathway in the mitochondria could be seen, with a significant increase in mitochondrial permeability and cytochrome c release, whereas the mitochondrial membrane potential was decreased.These findings indicate that liriodenine could be considered as a promising anticancer agent.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

ABSTRACT
Enicosanthellum pulchrum is a tropical plant from Malaysia and belongs to the Annonaceae family. This plant is rich in isoquinoline alkaloids. In the present study, liriodenine, an isoquinoline alkaloid, was examined as a potential anticancer agent, particularly in ovarian cancer. Liriodenine was isolated by preparative high-performance liquid chromatography. Cell viability was performed to determine the cytotoxicity, whilst the detection of morphological changes was carried out by acridine orange/propidium iodide assay. Initial and late apoptosis was examined by Annexin V-fluorescein isothiocyanate and DNA laddering assays, respectively. The involvement of pathways was detected via caspase-3, caspase-8, and caspase-9 analyses. Confirmation of pathways was further performed in mitochondria using a cytotoxicity 3 assay. Apoptosis was confirmed at the protein level, including Bax, Bcl-2, and survivin, while interruption of the cell cycle was used for final validation of apoptosis. The result showed that liriodenine inhibits proliferation of CAOV-3 cells at 37.3 μM after 24 hours of exposure. Changes in cell morphology were detected by the presence of cell membrane blebbing, chromatin condensation, and formation of apoptotic bodies. Early apoptosis was observed by Annexin V-fluorescein isothiocyanate bound to the cell membrane as early as 24 hours. Liriodenine activated the intrinsic pathway by induction of caspase-3 and caspase-9. Involvement of the intrinsic pathway in the mitochondria could be seen, with a significant increase in mitochondrial permeability and cytochrome c release, whereas the mitochondrial membrane potential was decreased. DNA fragmentation occurred at 72 hours upon exposure to liriodenine. The presence of DNA fragmentation indicates the CAOV-3 cells undergo late apoptosis or final stage of apoptosis. Confirmation of apoptosis at the protein level showed overexpression of Bax and suppression of Bcl-2 and survivin. Liriodenine inhibits progression of the CAOV-3 cell cycle in S phase. These findings indicate that liriodenine could be considered as a promising anticancer agent.

No MeSH data available.


Related in: MedlinePlus

IC50 value of liriodenine at different time points in a CAOV-3 cell line.
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f2-dddt-9-1437: IC50 value of liriodenine at different time points in a CAOV-3 cell line.

Mentions: The cytotoxic effects of liriodenine were studied in CAOV-3, SKOV-3, and normal ovarian (WRL-68 and SV-40) cell lines. Two standard drugs, paclitaxel and cisplatin, were used as positive controls in this experiment (Table 2). The IC50 results show that liriodenine inhibited CAOV-3 cell growth at a concentration of 37.3±1.06 μM after 24 hours of exposure. However, the IC50 concentration decreased after the cells were exposed to liriodenine at 48 and 72 hours, with values of 26.3±0.07 μM and 23.1±1.62 μM, respectively (Figure 2). The effect of liriodenine on CAOV-3 was significant when compared with cisplatin as a standard drug. Meanwhile, liriodenine exhibited less activity in SKOV-3 cells, with IC50 values of 68.0±1.56, 61.1±3.09, and 46.5±1.55 μM at 24, 48, and 72 hours, respectively. Additionally, both the normal ovarian cell lines displayed no evidence of cytotoxicity at a concentration higher than 100 μM.


Liriodenine, an aporphine alkaloid from Enicosanthellum pulchrum, inhibits proliferation of human ovarian cancer cells through induction of apoptosis via the mitochondrial signaling pathway and blocking cell cycle progression.

Nordin N, Majid NA, Hashim NM, Rahman MA, Hassan Z, Ali HM - Drug Des Devel Ther (2015)

IC50 value of liriodenine at different time points in a CAOV-3 cell line.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362660&req=5

f2-dddt-9-1437: IC50 value of liriodenine at different time points in a CAOV-3 cell line.
Mentions: The cytotoxic effects of liriodenine were studied in CAOV-3, SKOV-3, and normal ovarian (WRL-68 and SV-40) cell lines. Two standard drugs, paclitaxel and cisplatin, were used as positive controls in this experiment (Table 2). The IC50 results show that liriodenine inhibited CAOV-3 cell growth at a concentration of 37.3±1.06 μM after 24 hours of exposure. However, the IC50 concentration decreased after the cells were exposed to liriodenine at 48 and 72 hours, with values of 26.3±0.07 μM and 23.1±1.62 μM, respectively (Figure 2). The effect of liriodenine on CAOV-3 was significant when compared with cisplatin as a standard drug. Meanwhile, liriodenine exhibited less activity in SKOV-3 cells, with IC50 values of 68.0±1.56, 61.1±3.09, and 46.5±1.55 μM at 24, 48, and 72 hours, respectively. Additionally, both the normal ovarian cell lines displayed no evidence of cytotoxicity at a concentration higher than 100 μM.

Bottom Line: The result showed that liriodenine inhibits proliferation of CAOV-3 cells at 37.3 μM after 24 hours of exposure.Involvement of the intrinsic pathway in the mitochondria could be seen, with a significant increase in mitochondrial permeability and cytochrome c release, whereas the mitochondrial membrane potential was decreased.These findings indicate that liriodenine could be considered as a promising anticancer agent.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

ABSTRACT
Enicosanthellum pulchrum is a tropical plant from Malaysia and belongs to the Annonaceae family. This plant is rich in isoquinoline alkaloids. In the present study, liriodenine, an isoquinoline alkaloid, was examined as a potential anticancer agent, particularly in ovarian cancer. Liriodenine was isolated by preparative high-performance liquid chromatography. Cell viability was performed to determine the cytotoxicity, whilst the detection of morphological changes was carried out by acridine orange/propidium iodide assay. Initial and late apoptosis was examined by Annexin V-fluorescein isothiocyanate and DNA laddering assays, respectively. The involvement of pathways was detected via caspase-3, caspase-8, and caspase-9 analyses. Confirmation of pathways was further performed in mitochondria using a cytotoxicity 3 assay. Apoptosis was confirmed at the protein level, including Bax, Bcl-2, and survivin, while interruption of the cell cycle was used for final validation of apoptosis. The result showed that liriodenine inhibits proliferation of CAOV-3 cells at 37.3 μM after 24 hours of exposure. Changes in cell morphology were detected by the presence of cell membrane blebbing, chromatin condensation, and formation of apoptotic bodies. Early apoptosis was observed by Annexin V-fluorescein isothiocyanate bound to the cell membrane as early as 24 hours. Liriodenine activated the intrinsic pathway by induction of caspase-3 and caspase-9. Involvement of the intrinsic pathway in the mitochondria could be seen, with a significant increase in mitochondrial permeability and cytochrome c release, whereas the mitochondrial membrane potential was decreased. DNA fragmentation occurred at 72 hours upon exposure to liriodenine. The presence of DNA fragmentation indicates the CAOV-3 cells undergo late apoptosis or final stage of apoptosis. Confirmation of apoptosis at the protein level showed overexpression of Bax and suppression of Bcl-2 and survivin. Liriodenine inhibits progression of the CAOV-3 cell cycle in S phase. These findings indicate that liriodenine could be considered as a promising anticancer agent.

No MeSH data available.


Related in: MedlinePlus