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A novel derivative of doxorubicin, AD198, inhibits canine transitional cell carcinoma and osteosarcoma cells in vitro.

Rathore K, Cekanova M - Drug Des Devel Ther (2015)

Bottom Line: Because of the adverse effects of DOX, including hair loss, nausea, vomiting, liver dysfunction, and cardiotoxicity, novel derivatives of DOX have been synthesized and validated.AD198 had lower IC50 values as compared to DOX for all tested K9TCC and K9OSA cell lines.In addition, AD198 cleaved PKC-δ, which subsequently activated the p38 signaling pathway, resulting in the apoptosis of tested K9TCC and K9OSA cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA.

ABSTRACT
Doxorubicin (DOX) is one of the most commonly used chemotherapeutic treatments for a wide range of cancers. N-benzyladriamycin-14-valerate (AD198) is a lipophilic anthracycline that has been shown to target conventional and novel isoforms of protein kinase C (PKC) in cytoplasm of cells. Because of the adverse effects of DOX, including hair loss, nausea, vomiting, liver dysfunction, and cardiotoxicity, novel derivatives of DOX have been synthesized and validated. In this study, we evaluated the effects of DOX and its derivative, AD198, on cell viability of three canine transitional cell carcinoma (K9TCC) (K9TCC#1-Lillie, K9TCC#2-Dakota, K9TCC#4-Molly) and three canine osteosarcoma (K9OSA) (K9OSA#1-Zoe, K9OSA#2-Nashville, K9OSA#3-JJ) primary cancer cell lines. DOX and AD198 significantly inhibited cell proliferation in all tested K9TCC and K9OSA cell lines in a dose-dependent manner. AD198 inhibited cell viability of tested K9TCC and K9OSA cell lines more efficiently as compared to DOX at the same concentration using MTS (3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2h-tetrazolium) assay. AD198 had lower IC50 values as compared to DOX for all tested K9TCC and K9OSA cell lines. In addition, AD198 increased apoptosis in all tested K9TCC and K9OSA cell lines. AD198 increased the caspase activity in tested K9TCC and K9OSA cell lines, which was confirmed by caspase-3/7 assay, and cleavage of poly (ADP-ribose) polymerase (PARP) was confirmed by Western blotting analysis. In addition, AD198 cleaved PKC-δ, which subsequently activated the p38 signaling pathway, resulting in the apoptosis of tested K9TCC and K9OSA cell lines. Inhibition of the p38 signaling pathway by SB203580 rescued DOX- and AD198-induced apoptosis in tested K9TCC and K9OSA cell lines. Our in vitro results suggest that AD198 might be considered as a new treatment option for K9TCC and K9OSA cell lines cancers in vivo.

No MeSH data available.


Related in: MedlinePlus

DOX- and AD198 (AD)-inhibited cell viability of tested K9TCC and K9OSA cell lines.Notes: (A) K9TCC#1-Lillie, K9TCC#2-Dakota, and K9TCC#4-Molly and (B) K9OSA#1-Zoe, K9OSA#2-Nashville, K9OSA#3-JJ cells were treated with DOX (dark bars) and AD (white bars) at 0, 0.1, 0.5, and 1 μM for 48 hours and compared to control groups. Cell proliferation was determined by MTS assay and relative cell growth rate was normalized to control groups. Values represent mean ± standard error (n=16) of four replicates from four independent experiments. Paired Student’s t-tests comparing DOX treatment to control (#P<0.05, ##P<0.01, ###P<0.001), AD treatment to control ($P<0.05, $$P<0.01, $$$P<0.001), and AD to DOX treatment groups with the same dose treatment (*P<0.05, **P<0.01, ***P<0.001) were used.Abbreviations: AD, AD198; DOX, doxorubicin; K9OSA, canine osteosarcoma; K9TCC, canine transitional cell carcinoma; MTS, 3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium.
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f2-dddt-9-5323: DOX- and AD198 (AD)-inhibited cell viability of tested K9TCC and K9OSA cell lines.Notes: (A) K9TCC#1-Lillie, K9TCC#2-Dakota, and K9TCC#4-Molly and (B) K9OSA#1-Zoe, K9OSA#2-Nashville, K9OSA#3-JJ cells were treated with DOX (dark bars) and AD (white bars) at 0, 0.1, 0.5, and 1 μM for 48 hours and compared to control groups. Cell proliferation was determined by MTS assay and relative cell growth rate was normalized to control groups. Values represent mean ± standard error (n=16) of four replicates from four independent experiments. Paired Student’s t-tests comparing DOX treatment to control (#P<0.05, ##P<0.01, ###P<0.001), AD treatment to control ($P<0.05, $$P<0.01, $$$P<0.001), and AD to DOX treatment groups with the same dose treatment (*P<0.05, **P<0.01, ***P<0.001) were used.Abbreviations: AD, AD198; DOX, doxorubicin; K9OSA, canine osteosarcoma; K9TCC, canine transitional cell carcinoma; MTS, 3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium.

Mentions: AD198 targets PKC in nonnuclear cellular compartments14 and inhibits cell proliferation. Tested K9TCC and K9OSA cell lines were treated with 0.1, 0.5, and 1 μM of DOX and AD198 for 48 hours, as shown in Figure 2. Both DOX and AD198 significantly reduced the proliferation of tested K9TCC (Figure 2A) and K9OSA (Figure 2B) cells. AD198 was significantly more effective in inhibition of cell viability of tested K9TCC and K9OSA cell lines as compared to DOX at the same concentration (P<0.001) (Figure 2). IC50 values were calculated for DOX and AD198 for K9TCC#1-Lillie, K9TCC#2-Dakota, K9TCC#4-Molly, K9OSA#1-Zoe, K9OSA#2-Nashville, K9OSA#3-JJ, as shown in Table 2. The IC50 values for AD198 were lower than those for DOX in all tested cell lines. K9TCC#4-Molly and K9OSA#3-JJ cells were among the less responsive cells to therapy as compared to other cells, as shown in Figure 2 and Table 2.


A novel derivative of doxorubicin, AD198, inhibits canine transitional cell carcinoma and osteosarcoma cells in vitro.

Rathore K, Cekanova M - Drug Des Devel Ther (2015)

DOX- and AD198 (AD)-inhibited cell viability of tested K9TCC and K9OSA cell lines.Notes: (A) K9TCC#1-Lillie, K9TCC#2-Dakota, and K9TCC#4-Molly and (B) K9OSA#1-Zoe, K9OSA#2-Nashville, K9OSA#3-JJ cells were treated with DOX (dark bars) and AD (white bars) at 0, 0.1, 0.5, and 1 μM for 48 hours and compared to control groups. Cell proliferation was determined by MTS assay and relative cell growth rate was normalized to control groups. Values represent mean ± standard error (n=16) of four replicates from four independent experiments. Paired Student’s t-tests comparing DOX treatment to control (#P<0.05, ##P<0.01, ###P<0.001), AD treatment to control ($P<0.05, $$P<0.01, $$$P<0.001), and AD to DOX treatment groups with the same dose treatment (*P<0.05, **P<0.01, ***P<0.001) were used.Abbreviations: AD, AD198; DOX, doxorubicin; K9OSA, canine osteosarcoma; K9TCC, canine transitional cell carcinoma; MTS, 3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium.
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f2-dddt-9-5323: DOX- and AD198 (AD)-inhibited cell viability of tested K9TCC and K9OSA cell lines.Notes: (A) K9TCC#1-Lillie, K9TCC#2-Dakota, and K9TCC#4-Molly and (B) K9OSA#1-Zoe, K9OSA#2-Nashville, K9OSA#3-JJ cells were treated with DOX (dark bars) and AD (white bars) at 0, 0.1, 0.5, and 1 μM for 48 hours and compared to control groups. Cell proliferation was determined by MTS assay and relative cell growth rate was normalized to control groups. Values represent mean ± standard error (n=16) of four replicates from four independent experiments. Paired Student’s t-tests comparing DOX treatment to control (#P<0.05, ##P<0.01, ###P<0.001), AD treatment to control ($P<0.05, $$P<0.01, $$$P<0.001), and AD to DOX treatment groups with the same dose treatment (*P<0.05, **P<0.01, ***P<0.001) were used.Abbreviations: AD, AD198; DOX, doxorubicin; K9OSA, canine osteosarcoma; K9TCC, canine transitional cell carcinoma; MTS, 3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium.
Mentions: AD198 targets PKC in nonnuclear cellular compartments14 and inhibits cell proliferation. Tested K9TCC and K9OSA cell lines were treated with 0.1, 0.5, and 1 μM of DOX and AD198 for 48 hours, as shown in Figure 2. Both DOX and AD198 significantly reduced the proliferation of tested K9TCC (Figure 2A) and K9OSA (Figure 2B) cells. AD198 was significantly more effective in inhibition of cell viability of tested K9TCC and K9OSA cell lines as compared to DOX at the same concentration (P<0.001) (Figure 2). IC50 values were calculated for DOX and AD198 for K9TCC#1-Lillie, K9TCC#2-Dakota, K9TCC#4-Molly, K9OSA#1-Zoe, K9OSA#2-Nashville, K9OSA#3-JJ, as shown in Table 2. The IC50 values for AD198 were lower than those for DOX in all tested cell lines. K9TCC#4-Molly and K9OSA#3-JJ cells were among the less responsive cells to therapy as compared to other cells, as shown in Figure 2 and Table 2.

Bottom Line: Because of the adverse effects of DOX, including hair loss, nausea, vomiting, liver dysfunction, and cardiotoxicity, novel derivatives of DOX have been synthesized and validated.AD198 had lower IC50 values as compared to DOX for all tested K9TCC and K9OSA cell lines.In addition, AD198 cleaved PKC-δ, which subsequently activated the p38 signaling pathway, resulting in the apoptosis of tested K9TCC and K9OSA cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA.

ABSTRACT
Doxorubicin (DOX) is one of the most commonly used chemotherapeutic treatments for a wide range of cancers. N-benzyladriamycin-14-valerate (AD198) is a lipophilic anthracycline that has been shown to target conventional and novel isoforms of protein kinase C (PKC) in cytoplasm of cells. Because of the adverse effects of DOX, including hair loss, nausea, vomiting, liver dysfunction, and cardiotoxicity, novel derivatives of DOX have been synthesized and validated. In this study, we evaluated the effects of DOX and its derivative, AD198, on cell viability of three canine transitional cell carcinoma (K9TCC) (K9TCC#1-Lillie, K9TCC#2-Dakota, K9TCC#4-Molly) and three canine osteosarcoma (K9OSA) (K9OSA#1-Zoe, K9OSA#2-Nashville, K9OSA#3-JJ) primary cancer cell lines. DOX and AD198 significantly inhibited cell proliferation in all tested K9TCC and K9OSA cell lines in a dose-dependent manner. AD198 inhibited cell viability of tested K9TCC and K9OSA cell lines more efficiently as compared to DOX at the same concentration using MTS (3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2h-tetrazolium) assay. AD198 had lower IC50 values as compared to DOX for all tested K9TCC and K9OSA cell lines. In addition, AD198 increased apoptosis in all tested K9TCC and K9OSA cell lines. AD198 increased the caspase activity in tested K9TCC and K9OSA cell lines, which was confirmed by caspase-3/7 assay, and cleavage of poly (ADP-ribose) polymerase (PARP) was confirmed by Western blotting analysis. In addition, AD198 cleaved PKC-δ, which subsequently activated the p38 signaling pathway, resulting in the apoptosis of tested K9TCC and K9OSA cell lines. Inhibition of the p38 signaling pathway by SB203580 rescued DOX- and AD198-induced apoptosis in tested K9TCC and K9OSA cell lines. Our in vitro results suggest that AD198 might be considered as a new treatment option for K9TCC and K9OSA cell lines cancers in vivo.

No MeSH data available.


Related in: MedlinePlus