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Anticancer activities of self-assembled molecular bowls containing a phenanthrene-based donor and Ru(II) acceptors.

Kim I, Song YH, Singh N, Jeong YJ, Kwon JE, Kim H, Cho YM, Kang SC, Chi KW - Int J Nanomedicine (2015)

Bottom Line: The structure of the representative molecular bowl 5 was confirmed by single-crystal X-ray diffraction analysis.Bowl 6 also induced autophagosome formation via upregulation of p62 and promotion of the conversion of LC3-I to LC3-II.Moreover, bowl 6 promoted apoptotic cell death through downregulation of Akt/mTOR activation, followed by increased caspase-3 activity.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Bio-Resources, Yongin-si, Gyeonggi-Do, Republic of Korea.

ABSTRACT
Nano-sized multinuclear ruthenium complexes have rapidly emerged as promising therapeutic candidates with unique anticancer activities. Here, we describe the coordination-driven self-assembly and anticancer activities of a set of three organometallic tetranuclear Ru(II) molecular bowls. [2+2] Coordination-driven self-assembly of 3, 6-bis(pyridin-3- ylethynyl) phenanthrene (bpep) (1) and one of the three dinuclear arene ruthenium clips, [(η6-p-iPrC6H4Me)2Ru2-(OO\OO)][OTf]2 (OO\OO =2, 5-dioxido-1, 4-benzoquinonato, OTf = triflate) (2), 5, 8-dioxido-1, 4-naphthoquinonato (3), or 6, 11-dioxido-5, 12-naphthacenediona (4), resulted in three molecular bowls 5-7 of general formula [{(η6-p-iPrC6H4Me)2Ru2-(OO\OO)}2(bpep)2][OTf]4. All molecular bowls were obtained as triflate salts in very good yields (>90%) and were fully characterized using multinuclear nuclear magnetic resonance (NMR), electrospray ionization-mass spectrometry (ESI-MS), and elemental analysis. The structure of the representative molecular bowl 5 was confirmed by single-crystal X-ray diffraction analysis. The anticancer activities of molecular bowls 5-7 were determined by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide, autophagy, and Western blot analysis. Bowl 6 showed the strongest cytotoxicity in AGS human gastric carcinoma cells and was more cytotoxic than doxorubicin. In addition, autophagic activity and the ratio of apoptotic cell death increased in AGS cells by treatment with bowl 6. Bowl 6 also induced autophagosome formation via upregulation of p62 and promotion of the conversion of LC3-I to LC3-II. Moreover, bowl 6 promoted apoptotic cell death through downregulation of Akt/mTOR activation, followed by increased caspase-3 activity. These results suggest that bowl 6 induces gastric cancer cell death via modulation of autophagy and apoptosis. Bowl 6 is a potent anticancer agent and a potential treatment for human gastric cancer that merits further study.

No MeSH data available.


Related in: MedlinePlus

Caspase-3 activity in AGS cells following treatment with bowl 6.Note: Caspase-3 activity was evaluated by a luminescence assay. The results are mean ± standard error of mean (SEM) of triplicates from a representative experiment. **P<0.01 compared to control.
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f7-ijn-10-143: Caspase-3 activity in AGS cells following treatment with bowl 6.Note: Caspase-3 activity was evaluated by a luminescence assay. The results are mean ± standard error of mean (SEM) of triplicates from a representative experiment. **P<0.01 compared to control.

Mentions: To further elucidate the mechanisms underlying bowl 6–induced apoptosis in AGS cells, we assessed phosphorylation of Akt and mTOR proteins by Western blotting. In human cancers, activation of the Akt/mTOR pathway via phosphorylation leads to cancer cell proliferation and metastasis, while stimulating autophagy. Because inhibition of the Akt/mTOR pathway is associated with inhibition of autophagy in cancer cells, potential anticancer agents can maintain tumor survival or induce tumor growth.12, 41–43 Expression of p-Akt in the bowl 6–treated AGS cells significantly decreased in comparison with that in the untreated cells, which was in accordance with the downregulation of mTOR in comparison with the untreated cells (Figure 6B). To assess whether bowl 6 induced caspase-mediated apoptosis, caspase-3 activity was measured using a substrate cleavage–based assay. As shown Figure 7, bowl 6 significantly increased caspase-3 activity in a dose-dependent manner in comparison with that of the untreated cells. These results imply that bowl 6 induced cancer cell death by inhibiting the Akt/mTOR pathway, followed by activation of autophagy.


Anticancer activities of self-assembled molecular bowls containing a phenanthrene-based donor and Ru(II) acceptors.

Kim I, Song YH, Singh N, Jeong YJ, Kwon JE, Kim H, Cho YM, Kang SC, Chi KW - Int J Nanomedicine (2015)

Caspase-3 activity in AGS cells following treatment with bowl 6.Note: Caspase-3 activity was evaluated by a luminescence assay. The results are mean ± standard error of mean (SEM) of triplicates from a representative experiment. **P<0.01 compared to control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554412&req=5

f7-ijn-10-143: Caspase-3 activity in AGS cells following treatment with bowl 6.Note: Caspase-3 activity was evaluated by a luminescence assay. The results are mean ± standard error of mean (SEM) of triplicates from a representative experiment. **P<0.01 compared to control.
Mentions: To further elucidate the mechanisms underlying bowl 6–induced apoptosis in AGS cells, we assessed phosphorylation of Akt and mTOR proteins by Western blotting. In human cancers, activation of the Akt/mTOR pathway via phosphorylation leads to cancer cell proliferation and metastasis, while stimulating autophagy. Because inhibition of the Akt/mTOR pathway is associated with inhibition of autophagy in cancer cells, potential anticancer agents can maintain tumor survival or induce tumor growth.12, 41–43 Expression of p-Akt in the bowl 6–treated AGS cells significantly decreased in comparison with that in the untreated cells, which was in accordance with the downregulation of mTOR in comparison with the untreated cells (Figure 6B). To assess whether bowl 6 induced caspase-mediated apoptosis, caspase-3 activity was measured using a substrate cleavage–based assay. As shown Figure 7, bowl 6 significantly increased caspase-3 activity in a dose-dependent manner in comparison with that of the untreated cells. These results imply that bowl 6 induced cancer cell death by inhibiting the Akt/mTOR pathway, followed by activation of autophagy.

Bottom Line: The structure of the representative molecular bowl 5 was confirmed by single-crystal X-ray diffraction analysis.Bowl 6 also induced autophagosome formation via upregulation of p62 and promotion of the conversion of LC3-I to LC3-II.Moreover, bowl 6 promoted apoptotic cell death through downregulation of Akt/mTOR activation, followed by increased caspase-3 activity.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Bio-Resources, Yongin-si, Gyeonggi-Do, Republic of Korea.

ABSTRACT
Nano-sized multinuclear ruthenium complexes have rapidly emerged as promising therapeutic candidates with unique anticancer activities. Here, we describe the coordination-driven self-assembly and anticancer activities of a set of three organometallic tetranuclear Ru(II) molecular bowls. [2+2] Coordination-driven self-assembly of 3, 6-bis(pyridin-3- ylethynyl) phenanthrene (bpep) (1) and one of the three dinuclear arene ruthenium clips, [(η6-p-iPrC6H4Me)2Ru2-(OO\OO)][OTf]2 (OO\OO =2, 5-dioxido-1, 4-benzoquinonato, OTf = triflate) (2), 5, 8-dioxido-1, 4-naphthoquinonato (3), or 6, 11-dioxido-5, 12-naphthacenediona (4), resulted in three molecular bowls 5-7 of general formula [{(η6-p-iPrC6H4Me)2Ru2-(OO\OO)}2(bpep)2][OTf]4. All molecular bowls were obtained as triflate salts in very good yields (>90%) and were fully characterized using multinuclear nuclear magnetic resonance (NMR), electrospray ionization-mass spectrometry (ESI-MS), and elemental analysis. The structure of the representative molecular bowl 5 was confirmed by single-crystal X-ray diffraction analysis. The anticancer activities of molecular bowls 5-7 were determined by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide, autophagy, and Western blot analysis. Bowl 6 showed the strongest cytotoxicity in AGS human gastric carcinoma cells and was more cytotoxic than doxorubicin. In addition, autophagic activity and the ratio of apoptotic cell death increased in AGS cells by treatment with bowl 6. Bowl 6 also induced autophagosome formation via upregulation of p62 and promotion of the conversion of LC3-I to LC3-II. Moreover, bowl 6 promoted apoptotic cell death through downregulation of Akt/mTOR activation, followed by increased caspase-3 activity. These results suggest that bowl 6 induces gastric cancer cell death via modulation of autophagy and apoptosis. Bowl 6 is a potent anticancer agent and a potential treatment for human gastric cancer that merits further study.

No MeSH data available.


Related in: MedlinePlus