Limits...
Novel Etoposide Analogue Modulates Expression of Angiogenesis Associated microRNAs and Regulates Cell Proliferation by Targeting STAT3 in Breast Cancer.

Srinivas C, Ramaiah MJ, Lavanya A, Yerramsetty S, Kavi Kishor PB, Basha SA, Kamal A, Bhadra U, Bhadra MP - PLoS ONE (2015)

Bottom Line: We developed a novel Etoposide analogue, Quinazolino-4β-amidopodophyllotoxin (C-10) that show better efficacy in regulating cell proliferation and angiogenesis.Docking studies clearly demonstrated the binding of Etoposide and C-10 to STAT3.We conclude that combination of Etoposide or C-10 with miR-15, 16, 17 and 221 as a new approach to induce apoptosis and control angiogenesis in breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.

ABSTRACT
Tumor microenvironment play role in angiogenesis and carcinogenesis. Etoposide, a known topoisomerase II inhibitor induces DNA damage resulting in cell cycle arrest. We developed a novel Etoposide analogue, Quinazolino-4β-amidopodophyllotoxin (C-10) that show better efficacy in regulating cell proliferation and angiogenesis. We evaluated its role on expression of microRNAs-15, 16, 17 and 221 and its targets Bcl-2, STAT3 and VEGF that dictate cell proliferation and angiogenesis. Docking studies clearly demonstrated the binding of Etoposide and C-10 to STAT3. We conclude that combination of Etoposide or C-10 with miR-15, 16, 17 and 221 as a new approach to induce apoptosis and control angiogenesis in breast cancer.

No MeSH data available.


Related in: MedlinePlus

Chemical structure and anti-cancer activities of Etoposide and C-10 on breast cancer cells.(A) Chemical structure of Etoposide and C-10 [4β-[6-(3, 4-dichlorophenyl) 3, 4-dihydro-2-methyl-4-oxoquinazolin-6-yloxy) hexanamide]-4-desoxy-podophyllotoxin]. (B) Trypan blue assay for cell viability on MCF-7 and MDA-MB-231 cells showing gradual decrease in viability after treatment with Etoposide or C-10 at 1–16 μM or Cisplatin at 5–40 μM and incubated for 24 h. (C) HUVEC cells were grown on EGM media and treated with Cisplatin, Etoposide or C-10 compounds after tube formation. Drastic inhibitory effect was observed upon C-10 treatment. (D) Wound healing assay on MCF-7 and MDA-MB-231 cells showing antiangiogenic and antimigratory effects after treatment with C-10 for 48 h. Images were obtained at 0 h, 24 h and 48 h by using an inverted microscope with 4X objective lens.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4638343&req=5

pone.0142006.g001: Chemical structure and anti-cancer activities of Etoposide and C-10 on breast cancer cells.(A) Chemical structure of Etoposide and C-10 [4β-[6-(3, 4-dichlorophenyl) 3, 4-dihydro-2-methyl-4-oxoquinazolin-6-yloxy) hexanamide]-4-desoxy-podophyllotoxin]. (B) Trypan blue assay for cell viability on MCF-7 and MDA-MB-231 cells showing gradual decrease in viability after treatment with Etoposide or C-10 at 1–16 μM or Cisplatin at 5–40 μM and incubated for 24 h. (C) HUVEC cells were grown on EGM media and treated with Cisplatin, Etoposide or C-10 compounds after tube formation. Drastic inhibitory effect was observed upon C-10 treatment. (D) Wound healing assay on MCF-7 and MDA-MB-231 cells showing antiangiogenic and antimigratory effects after treatment with C-10 for 48 h. Images were obtained at 0 h, 24 h and 48 h by using an inverted microscope with 4X objective lens.

Mentions: We measured the toxic effect of Quinazolino-4β-amidopodophyllotoxin (C-10) on cell viability in MCF-7 and MDA-MB-231 breast cancer cell lines. Trypan blue assay based on the principle that live cells with intact cell membrane excludes the trypan blue, whereas dead cells do not was performed. The MCF-7 and MDA-MB-231 cells were treated with Etoposide or C-10 at 1–16 μM and Cisplatin at 5–40 μM and incubated for 24 h. There was a 50% reduction in cell viability when treated with Etoposide or C-10 at 4 μM concentration and Cisplatin at 30 μM (Fig 1B). Previous studies with deoxy-podophyllotoxin conjugates have shown inhibitory activity on angiogenic tube formation in HUVEC cells and exhibited cytotoxic effects in A549, SK-OV-3, SK-MEL-2, HCT-15 and B16F10 cancer cells [29, 30]. Thus, we quantified the potential inhibitory activity of C-10 on angiogenesis by conducting in vitro angiogenic assay. HUVEC cells were seeded on matrigel and allowed to form capillary tube like network for 6 h followed by treatment with Cisplatin, Etoposide or C-10. Images were observed under microscope and analyzed. Interestingly, C-10 treated HUVEC cells resulted in drastic decrease in the percentage of tube formation compared to Cisplatin and Etoposide confirming its effective role in angiogenesis (Fig 1C).


Novel Etoposide Analogue Modulates Expression of Angiogenesis Associated microRNAs and Regulates Cell Proliferation by Targeting STAT3 in Breast Cancer.

Srinivas C, Ramaiah MJ, Lavanya A, Yerramsetty S, Kavi Kishor PB, Basha SA, Kamal A, Bhadra U, Bhadra MP - PLoS ONE (2015)

Chemical structure and anti-cancer activities of Etoposide and C-10 on breast cancer cells.(A) Chemical structure of Etoposide and C-10 [4β-[6-(3, 4-dichlorophenyl) 3, 4-dihydro-2-methyl-4-oxoquinazolin-6-yloxy) hexanamide]-4-desoxy-podophyllotoxin]. (B) Trypan blue assay for cell viability on MCF-7 and MDA-MB-231 cells showing gradual decrease in viability after treatment with Etoposide or C-10 at 1–16 μM or Cisplatin at 5–40 μM and incubated for 24 h. (C) HUVEC cells were grown on EGM media and treated with Cisplatin, Etoposide or C-10 compounds after tube formation. Drastic inhibitory effect was observed upon C-10 treatment. (D) Wound healing assay on MCF-7 and MDA-MB-231 cells showing antiangiogenic and antimigratory effects after treatment with C-10 for 48 h. Images were obtained at 0 h, 24 h and 48 h by using an inverted microscope with 4X objective lens.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4638343&req=5

pone.0142006.g001: Chemical structure and anti-cancer activities of Etoposide and C-10 on breast cancer cells.(A) Chemical structure of Etoposide and C-10 [4β-[6-(3, 4-dichlorophenyl) 3, 4-dihydro-2-methyl-4-oxoquinazolin-6-yloxy) hexanamide]-4-desoxy-podophyllotoxin]. (B) Trypan blue assay for cell viability on MCF-7 and MDA-MB-231 cells showing gradual decrease in viability after treatment with Etoposide or C-10 at 1–16 μM or Cisplatin at 5–40 μM and incubated for 24 h. (C) HUVEC cells were grown on EGM media and treated with Cisplatin, Etoposide or C-10 compounds after tube formation. Drastic inhibitory effect was observed upon C-10 treatment. (D) Wound healing assay on MCF-7 and MDA-MB-231 cells showing antiangiogenic and antimigratory effects after treatment with C-10 for 48 h. Images were obtained at 0 h, 24 h and 48 h by using an inverted microscope with 4X objective lens.
Mentions: We measured the toxic effect of Quinazolino-4β-amidopodophyllotoxin (C-10) on cell viability in MCF-7 and MDA-MB-231 breast cancer cell lines. Trypan blue assay based on the principle that live cells with intact cell membrane excludes the trypan blue, whereas dead cells do not was performed. The MCF-7 and MDA-MB-231 cells were treated with Etoposide or C-10 at 1–16 μM and Cisplatin at 5–40 μM and incubated for 24 h. There was a 50% reduction in cell viability when treated with Etoposide or C-10 at 4 μM concentration and Cisplatin at 30 μM (Fig 1B). Previous studies with deoxy-podophyllotoxin conjugates have shown inhibitory activity on angiogenic tube formation in HUVEC cells and exhibited cytotoxic effects in A549, SK-OV-3, SK-MEL-2, HCT-15 and B16F10 cancer cells [29, 30]. Thus, we quantified the potential inhibitory activity of C-10 on angiogenesis by conducting in vitro angiogenic assay. HUVEC cells were seeded on matrigel and allowed to form capillary tube like network for 6 h followed by treatment with Cisplatin, Etoposide or C-10. Images were observed under microscope and analyzed. Interestingly, C-10 treated HUVEC cells resulted in drastic decrease in the percentage of tube formation compared to Cisplatin and Etoposide confirming its effective role in angiogenesis (Fig 1C).

Bottom Line: We developed a novel Etoposide analogue, Quinazolino-4β-amidopodophyllotoxin (C-10) that show better efficacy in regulating cell proliferation and angiogenesis.Docking studies clearly demonstrated the binding of Etoposide and C-10 to STAT3.We conclude that combination of Etoposide or C-10 with miR-15, 16, 17 and 221 as a new approach to induce apoptosis and control angiogenesis in breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.

ABSTRACT
Tumor microenvironment play role in angiogenesis and carcinogenesis. Etoposide, a known topoisomerase II inhibitor induces DNA damage resulting in cell cycle arrest. We developed a novel Etoposide analogue, Quinazolino-4β-amidopodophyllotoxin (C-10) that show better efficacy in regulating cell proliferation and angiogenesis. We evaluated its role on expression of microRNAs-15, 16, 17 and 221 and its targets Bcl-2, STAT3 and VEGF that dictate cell proliferation and angiogenesis. Docking studies clearly demonstrated the binding of Etoposide and C-10 to STAT3. We conclude that combination of Etoposide or C-10 with miR-15, 16, 17 and 221 as a new approach to induce apoptosis and control angiogenesis in breast cancer.

No MeSH data available.


Related in: MedlinePlus