Limits...
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

Effects of bowl 6 on programmed cell death.Notes: (A) The representative pictures of MDC, DAPI-stained cells with merged pictures in AGS cells. Cells were treated with 20 μM bowl 6 for 24 hours and DAPI or MDC staining was observed under fluorescence microscope. (B) Relative autophagic activity following exposure to bowl 6 in the AGS and COS-7 cell lines. The cells were treated with the samples for 24 hours. (C) Analysis of apoptotic cell death in the AGS and COS-7 cell lines. Live cells and apoptotic cells were stained red and green. Apoptosis was assessed using a Tali® Image-Based Cytometer (Thermo Fisher Scientific). The results are mean ± standard error of mean (SEM) of triplicates from a representative experiment. *P<0.05, **P<0.01 compared to 0.Abbreviation: MDC, monodansylcadaverine.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4554412&req=5

f5-ijn-10-143: Effects of bowl 6 on programmed cell death.Notes: (A) The representative pictures of MDC, DAPI-stained cells with merged pictures in AGS cells. Cells were treated with 20 μM bowl 6 for 24 hours and DAPI or MDC staining was observed under fluorescence microscope. (B) Relative autophagic activity following exposure to bowl 6 in the AGS and COS-7 cell lines. The cells were treated with the samples for 24 hours. (C) Analysis of apoptotic cell death in the AGS and COS-7 cell lines. Live cells and apoptotic cells were stained red and green. Apoptosis was assessed using a Tali® Image-Based Cytometer (Thermo Fisher Scientific). The results are mean ± standard error of mean (SEM) of triplicates from a representative experiment. *P<0.05, **P<0.01 compared to 0.Abbreviation: MDC, monodansylcadaverine.

Mentions: To investigate whether the cytotoxic effects of bowl 6 in AGS cells were mediated by autophagy or apoptotic cell death, we estimated relative autophagic activity. Green fluorescent protein–transduced cells were stained using the Tali® Viability Kit, while Dead Cell Red was used to stain AGS human gastric cancer cells and COS-7 normal monkey kidney fibroblast cells. Cells were treated with 20 μM Bowl 6 for 24 hours, and DAPI or MDC staining was observed under fluorescence microscope. The representative pictures showed that treatment of 20 μM Bowl 6 increased MDC-stained area compared to control cells, indicating that Bowl 6 stimulated the autophagic vacuoles (Figure 5A). As shown Figure 5B, bowl 6 at concentrations of 5 μM, 10 μM, and 20 μM significantly increased the autophagic activity of AGS cells by 27.1%, 48.6%, and 68.4%, respectively, in comparison with the untreated cells. In normal COS-7 cells, bowl 6 at concentrations of 5 μM, 10 μM, and 20 μM significantly increased autophagic activity by 12.5%, 18.9%, and 23.3%, respectively, in comparison with the untreated cells. At a concentration of 20 μM, bowl 6 significantly increased the autophagic activity of AGS cells by 1.4-fold in comparison with normal cells. As shown Figure 5C, bowl 6 markedly induced concentration-dependent apoptotic cell death in AGS cells, while normal COS-7 cells were less susceptible to bowl 6 and had a higher ratio of live cells than the AGS cells following treatment with the same concentration of bowl 6. These results suggest that bowl 6 is selectively cytotoxic to cancer cells via induction of autophagic activity and apoptotic cell death, while producing no significant changes in autophagy or apoptosis in normal fibroblasts.


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)

Effects of bowl 6 on programmed cell death.Notes: (A) The representative pictures of MDC, DAPI-stained cells with merged pictures in AGS cells. Cells were treated with 20 μM bowl 6 for 24 hours and DAPI or MDC staining was observed under fluorescence microscope. (B) Relative autophagic activity following exposure to bowl 6 in the AGS and COS-7 cell lines. The cells were treated with the samples for 24 hours. (C) Analysis of apoptotic cell death in the AGS and COS-7 cell lines. Live cells and apoptotic cells were stained red and green. Apoptosis was assessed using a Tali® Image-Based Cytometer (Thermo Fisher Scientific). The results are mean ± standard error of mean (SEM) of triplicates from a representative experiment. *P<0.05, **P<0.01 compared to 0.Abbreviation: MDC, monodansylcadaverine.
© Copyright Policy
Related In: Results  -  Collection

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

f5-ijn-10-143: Effects of bowl 6 on programmed cell death.Notes: (A) The representative pictures of MDC, DAPI-stained cells with merged pictures in AGS cells. Cells were treated with 20 μM bowl 6 for 24 hours and DAPI or MDC staining was observed under fluorescence microscope. (B) Relative autophagic activity following exposure to bowl 6 in the AGS and COS-7 cell lines. The cells were treated with the samples for 24 hours. (C) Analysis of apoptotic cell death in the AGS and COS-7 cell lines. Live cells and apoptotic cells were stained red and green. Apoptosis was assessed using a Tali® Image-Based Cytometer (Thermo Fisher Scientific). The results are mean ± standard error of mean (SEM) of triplicates from a representative experiment. *P<0.05, **P<0.01 compared to 0.Abbreviation: MDC, monodansylcadaverine.
Mentions: To investigate whether the cytotoxic effects of bowl 6 in AGS cells were mediated by autophagy or apoptotic cell death, we estimated relative autophagic activity. Green fluorescent protein–transduced cells were stained using the Tali® Viability Kit, while Dead Cell Red was used to stain AGS human gastric cancer cells and COS-7 normal monkey kidney fibroblast cells. Cells were treated with 20 μM Bowl 6 for 24 hours, and DAPI or MDC staining was observed under fluorescence microscope. The representative pictures showed that treatment of 20 μM Bowl 6 increased MDC-stained area compared to control cells, indicating that Bowl 6 stimulated the autophagic vacuoles (Figure 5A). As shown Figure 5B, bowl 6 at concentrations of 5 μM, 10 μM, and 20 μM significantly increased the autophagic activity of AGS cells by 27.1%, 48.6%, and 68.4%, respectively, in comparison with the untreated cells. In normal COS-7 cells, bowl 6 at concentrations of 5 μM, 10 μM, and 20 μM significantly increased autophagic activity by 12.5%, 18.9%, and 23.3%, respectively, in comparison with the untreated cells. At a concentration of 20 μM, bowl 6 significantly increased the autophagic activity of AGS cells by 1.4-fold in comparison with normal cells. As shown Figure 5C, bowl 6 markedly induced concentration-dependent apoptotic cell death in AGS cells, while normal COS-7 cells were less susceptible to bowl 6 and had a higher ratio of live cells than the AGS cells following treatment with the same concentration of bowl 6. These results suggest that bowl 6 is selectively cytotoxic to cancer cells via induction of autophagic activity and apoptotic cell death, while producing no significant changes in autophagy or apoptosis in normal fibroblasts.

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