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Anti-Proliferative and Pro-Apoptotic Activities of 4-Methyl-2,6-bis(1-phenylethyl)phenol in Cancer Cells.

Sung NY, Kim SC, Kim YH, Kim G, Lee Y, Sung GH, Kim JH, Yang WS, Kim MS, Baek KS, Kim JH, Cho JY - Biomol Ther (Seoul) (2016)

Bottom Line: It has been found that 4-isopropyl-2,6-bis(1-phenylethyl)phenol (KTH-13), a novel compound isolated from Cordyceps bassiana, is able to suppress tumor cell proliferation by inducing apoptosis.Moreover, KTH-13-Me highly enhanced the activation of caspase-3 and caspase-9, and decreased the protein level of Bcl-2.Therefore, these results suggest that KTH-13-Me can be developed as a novel anti-cancer drug capable of blocking proliferation, inducing apoptosis, and blocking cell survival signaling in cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.

ABSTRACT
It has been found that 4-isopropyl-2,6-bis(1-phenylethyl)phenol (KTH-13), a novel compound isolated from Cordyceps bassiana, is able to suppress tumor cell proliferation by inducing apoptosis. To mass-produce this compound, we established a total synthesis method. Using those conditions, we further synthesized various analogs with structural similarity to KTH-13. In this study, we aimed to test their anti-cancer activity by measuring anti-proliferative and pro-apoptotic activities. Of 8 compounds tested, 4-methyl-2,6-bis(1-phenylethyl)phenol (KTH-13-Me) exhibited the strongest anti-proliferative activity toward MDA-MB 231 cells. KTH-13-Me also similarly suppressed the survival of various cancer cell lines, including C6 glioma, HCT-15, and LoVo cells. Treatment of KTH-13-Me induced several apoptotic signs in C6 glioma cells, such as morphological changes, induction of apoptotic bodies, and nuclear fragmentation and chromatin condensation. Concordantly, early-apoptotic cells were also identified by staining with FITC-Annexin V/PI. Moreover, KTH-13-Me highly enhanced the activation of caspase-3 and caspase-9, and decreased the protein level of Bcl-2. In addition, the phosphorylation levels of Src and STAT3 were diminished in KTH-13-Me-treated C6 cells. Therefore, these results suggest that KTH-13-Me can be developed as a novel anti-cancer drug capable of blocking proliferation, inducing apoptosis, and blocking cell survival signaling in cancer cells.

No MeSH data available.


Related in: MedlinePlus

Effect of KTH-13-Me on the expression of apoptosis-related and cell survival regulatory proteins. (A and B) Enhanced levels of active apoptosis-related proteins (cleaved caspases-3 and -9) and activated cell survival-regulatory proteins (phospho-Src and phospho-STAT-3) in C6 glioma cells incubated with KTH-13-Me for 6 h were detected by immunoblotting analysis. Relative intensity was calculated using total levels with the DNR Bio-Imaging system. All of the data are expressed as the means ± SD of experiments that were performed with six or three samples. *p<0.05 and **p<0.01 compared to the control group.
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f4-bt-24-402: Effect of KTH-13-Me on the expression of apoptosis-related and cell survival regulatory proteins. (A and B) Enhanced levels of active apoptosis-related proteins (cleaved caspases-3 and -9) and activated cell survival-regulatory proteins (phospho-Src and phospho-STAT-3) in C6 glioma cells incubated with KTH-13-Me for 6 h were detected by immunoblotting analysis. Relative intensity was calculated using total levels with the DNR Bio-Imaging system. All of the data are expressed as the means ± SD of experiments that were performed with six or three samples. *p<0.05 and **p<0.01 compared to the control group.

Mentions: Based on a variety of evidence regarding the apoptosis-inducing activity of KTH-13-Me, we investigated the mechanism underlying its pro-apoptotic activity. As Fig. 4A indicates, caspase-3 and -9, well-known apoptosis-inducing factors (Orrenius, 2007), were cleaved into active forms in C6 glioma cells incubated with KTH-13-Me for 6 h. In addition, treatment with KTH-13-Me (40 μM) decreased the protein level of Bcl-2, an apoptosis-preventing protein (Igney and Krammer, 2002), in C6 glioma cells. Moreover, the activities of Src and STAT3 (which are proteins related to the expression of Bcl-2) were strongly suppressed by 40 μM KTH-13-Me, as indicated by their phosphorylation levels (Fig. 4B).


Anti-Proliferative and Pro-Apoptotic Activities of 4-Methyl-2,6-bis(1-phenylethyl)phenol in Cancer Cells.

Sung NY, Kim SC, Kim YH, Kim G, Lee Y, Sung GH, Kim JH, Yang WS, Kim MS, Baek KS, Kim JH, Cho JY - Biomol Ther (Seoul) (2016)

Effect of KTH-13-Me on the expression of apoptosis-related and cell survival regulatory proteins. (A and B) Enhanced levels of active apoptosis-related proteins (cleaved caspases-3 and -9) and activated cell survival-regulatory proteins (phospho-Src and phospho-STAT-3) in C6 glioma cells incubated with KTH-13-Me for 6 h were detected by immunoblotting analysis. Relative intensity was calculated using total levels with the DNR Bio-Imaging system. All of the data are expressed as the means ± SD of experiments that were performed with six or three samples. *p<0.05 and **p<0.01 compared to the control group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4930284&req=5

f4-bt-24-402: Effect of KTH-13-Me on the expression of apoptosis-related and cell survival regulatory proteins. (A and B) Enhanced levels of active apoptosis-related proteins (cleaved caspases-3 and -9) and activated cell survival-regulatory proteins (phospho-Src and phospho-STAT-3) in C6 glioma cells incubated with KTH-13-Me for 6 h were detected by immunoblotting analysis. Relative intensity was calculated using total levels with the DNR Bio-Imaging system. All of the data are expressed as the means ± SD of experiments that were performed with six or three samples. *p<0.05 and **p<0.01 compared to the control group.
Mentions: Based on a variety of evidence regarding the apoptosis-inducing activity of KTH-13-Me, we investigated the mechanism underlying its pro-apoptotic activity. As Fig. 4A indicates, caspase-3 and -9, well-known apoptosis-inducing factors (Orrenius, 2007), were cleaved into active forms in C6 glioma cells incubated with KTH-13-Me for 6 h. In addition, treatment with KTH-13-Me (40 μM) decreased the protein level of Bcl-2, an apoptosis-preventing protein (Igney and Krammer, 2002), in C6 glioma cells. Moreover, the activities of Src and STAT3 (which are proteins related to the expression of Bcl-2) were strongly suppressed by 40 μM KTH-13-Me, as indicated by their phosphorylation levels (Fig. 4B).

Bottom Line: It has been found that 4-isopropyl-2,6-bis(1-phenylethyl)phenol (KTH-13), a novel compound isolated from Cordyceps bassiana, is able to suppress tumor cell proliferation by inducing apoptosis.Moreover, KTH-13-Me highly enhanced the activation of caspase-3 and caspase-9, and decreased the protein level of Bcl-2.Therefore, these results suggest that KTH-13-Me can be developed as a novel anti-cancer drug capable of blocking proliferation, inducing apoptosis, and blocking cell survival signaling in cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.

ABSTRACT
It has been found that 4-isopropyl-2,6-bis(1-phenylethyl)phenol (KTH-13), a novel compound isolated from Cordyceps bassiana, is able to suppress tumor cell proliferation by inducing apoptosis. To mass-produce this compound, we established a total synthesis method. Using those conditions, we further synthesized various analogs with structural similarity to KTH-13. In this study, we aimed to test their anti-cancer activity by measuring anti-proliferative and pro-apoptotic activities. Of 8 compounds tested, 4-methyl-2,6-bis(1-phenylethyl)phenol (KTH-13-Me) exhibited the strongest anti-proliferative activity toward MDA-MB 231 cells. KTH-13-Me also similarly suppressed the survival of various cancer cell lines, including C6 glioma, HCT-15, and LoVo cells. Treatment of KTH-13-Me induced several apoptotic signs in C6 glioma cells, such as morphological changes, induction of apoptotic bodies, and nuclear fragmentation and chromatin condensation. Concordantly, early-apoptotic cells were also identified by staining with FITC-Annexin V/PI. Moreover, KTH-13-Me highly enhanced the activation of caspase-3 and caspase-9, and decreased the protein level of Bcl-2. In addition, the phosphorylation levels of Src and STAT3 were diminished in KTH-13-Me-treated C6 cells. Therefore, these results suggest that KTH-13-Me can be developed as a novel anti-cancer drug capable of blocking proliferation, inducing apoptosis, and blocking cell survival signaling in cancer cells.

No MeSH data available.


Related in: MedlinePlus