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Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid In vitro.

Qiao H, Wang TY, Yan W, Qin A, Fan QM, Han XG, Wang YG, Tang TT - Acta Pharmacol. Sin. (2015)

Bottom Line: Synergism was evaluated using Compusyn software, and the combination index (CI) and drug reduction index (DRI) values were determined.The DRI values also showed a synergistic effect between PL and ZA, with actual values of 5.52 and 3.59, respectively.Moreover, the combination of ZA and PL decreased the expression of Notch-1, cleaved PARP, Bcl-2 and Bcl-xl, and increased the expression of cleaved caspase-3, CDKN1A and ID1.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

ABSTRACT

Aim: Zoledronic acid (ZA), a bisphosphonate, is currently used in combination with chemotherapeutic agents to suppress breast cancer cell proliferation or breast cancer-induced osteolysis. The aim of this study was to investigate the effects of ZA combined with a natural anticancer compound plumbagin (PL) against human breast cancer cells in vitro.

Methods: Human breast cancer MDA-MB-231SArfp cells were treated with ZA, PL or a combination of ZA and PL. The cell growth, apoptosis and migration were evaluated using CCK-8 assay, flow cytometry and transwell assay, respectively. The expression of apoptosis-related proteins was measured using real-time PCR and Western blotting. Synergism was evaluated using Compusyn software, and the combination index (CI) and drug reduction index (DRI) values were determined.

Results: PL or ZA alone caused mild cytotoxicity (the IC50 value at 24 h was 12.18 and above 100 μmol/L, respectively). However, the combination of ZA and PL caused a synergistic cytotoxicity (CI=0.26). The DRI values also showed a synergistic effect between PL and ZA, with actual values of 5.52 and 3.59, respectively. Furthermore, PL and ZA synergistically induced apoptosis and inhibited migration of the breast cancer cells. Moreover, the combination of ZA and PL decreased the expression of Notch-1, cleaved PARP, Bcl-2 and Bcl-xl, and increased the expression of cleaved caspase-3, CDKN1A and ID1. When the breast cancer cells were transfected with specific siRNA against Notch-1, the combination of ZA and PL markedly increased the expression of Bcl-2.

Conclusion: Combination of ZA and PL synergistically suppresses human breast cancer MDA-MB-231SArfp cells in vitro. PL can inhibit ZA-induced activation of the Notch-1 signaling pathway and subsequently reduce the expression of Bcl-2, thus potentiating cancer cell apoptosis.

No MeSH data available.


Related in: MedlinePlus

Effects of plumbagin(PL) and zoledronic acid (ZA) alone or in combination on MDA-MB-231SArfp cell migration. (A, B) In vitro evaluation of MDA-MB-231SArfp cell migration after PL and ZA treatment alone. (C, D) Combined administration of PL and ZA significantly enhances the inhibition of tumor cell metastasis compared with individual treatment. All data represent the means±SD of at least three independent experiments. bP<0.05, cP<0.01.
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fig4: Effects of plumbagin(PL) and zoledronic acid (ZA) alone or in combination on MDA-MB-231SArfp cell migration. (A, B) In vitro evaluation of MDA-MB-231SArfp cell migration after PL and ZA treatment alone. (C, D) Combined administration of PL and ZA significantly enhances the inhibition of tumor cell metastasis compared with individual treatment. All data represent the means±SD of at least three independent experiments. bP<0.05, cP<0.01.

Mentions: Treatment with PL and ZA alone or in combination resulted in a dose-dependent decrease in cell migration with respect to the control group (Figure 4). These results indicated that the combination of PL and ZA exhibited a synergistic effect on MDA-MB-231SArfp cell metastasis and led to a significant decrease in the number of cells that penetrated to the bottom membrane of the transwell chamber. Both 25 and 50 μmol/L ZA displayed enhanced synergistic inhibitory ability irrespective of the PL concentration, and this was also demonstrated for 12.5 μmol/L ZA with 2.5 and 5 μmol/L PL. Nevertheless, 12.5 μmol/L ZA exhibited limited synergistic effects in the 10 μmol/L PL-treatment group. However, 2.5, 5, and 10 μmol/L PL increased the inhibition of tumor metastasis in all ZA-treatment groups. Thus, the metastasis of MDA-MB-231SArfp cells was significantly inhibited through a combination of PL and ZA compared with either agent alone.


Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid In vitro.

Qiao H, Wang TY, Yan W, Qin A, Fan QM, Han XG, Wang YG, Tang TT - Acta Pharmacol. Sin. (2015)

Effects of plumbagin(PL) and zoledronic acid (ZA) alone or in combination on MDA-MB-231SArfp cell migration. (A, B) In vitro evaluation of MDA-MB-231SArfp cell migration after PL and ZA treatment alone. (C, D) Combined administration of PL and ZA significantly enhances the inhibition of tumor cell metastasis compared with individual treatment. All data represent the means±SD of at least three independent experiments. bP<0.05, cP<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4561967&req=5

fig4: Effects of plumbagin(PL) and zoledronic acid (ZA) alone or in combination on MDA-MB-231SArfp cell migration. (A, B) In vitro evaluation of MDA-MB-231SArfp cell migration after PL and ZA treatment alone. (C, D) Combined administration of PL and ZA significantly enhances the inhibition of tumor cell metastasis compared with individual treatment. All data represent the means±SD of at least three independent experiments. bP<0.05, cP<0.01.
Mentions: Treatment with PL and ZA alone or in combination resulted in a dose-dependent decrease in cell migration with respect to the control group (Figure 4). These results indicated that the combination of PL and ZA exhibited a synergistic effect on MDA-MB-231SArfp cell metastasis and led to a significant decrease in the number of cells that penetrated to the bottom membrane of the transwell chamber. Both 25 and 50 μmol/L ZA displayed enhanced synergistic inhibitory ability irrespective of the PL concentration, and this was also demonstrated for 12.5 μmol/L ZA with 2.5 and 5 μmol/L PL. Nevertheless, 12.5 μmol/L ZA exhibited limited synergistic effects in the 10 μmol/L PL-treatment group. However, 2.5, 5, and 10 μmol/L PL increased the inhibition of tumor metastasis in all ZA-treatment groups. Thus, the metastasis of MDA-MB-231SArfp cells was significantly inhibited through a combination of PL and ZA compared with either agent alone.

Bottom Line: Synergism was evaluated using Compusyn software, and the combination index (CI) and drug reduction index (DRI) values were determined.The DRI values also showed a synergistic effect between PL and ZA, with actual values of 5.52 and 3.59, respectively.Moreover, the combination of ZA and PL decreased the expression of Notch-1, cleaved PARP, Bcl-2 and Bcl-xl, and increased the expression of cleaved caspase-3, CDKN1A and ID1.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

ABSTRACT

Aim: Zoledronic acid (ZA), a bisphosphonate, is currently used in combination with chemotherapeutic agents to suppress breast cancer cell proliferation or breast cancer-induced osteolysis. The aim of this study was to investigate the effects of ZA combined with a natural anticancer compound plumbagin (PL) against human breast cancer cells in vitro.

Methods: Human breast cancer MDA-MB-231SArfp cells were treated with ZA, PL or a combination of ZA and PL. The cell growth, apoptosis and migration were evaluated using CCK-8 assay, flow cytometry and transwell assay, respectively. The expression of apoptosis-related proteins was measured using real-time PCR and Western blotting. Synergism was evaluated using Compusyn software, and the combination index (CI) and drug reduction index (DRI) values were determined.

Results: PL or ZA alone caused mild cytotoxicity (the IC50 value at 24 h was 12.18 and above 100 μmol/L, respectively). However, the combination of ZA and PL caused a synergistic cytotoxicity (CI=0.26). The DRI values also showed a synergistic effect between PL and ZA, with actual values of 5.52 and 3.59, respectively. Furthermore, PL and ZA synergistically induced apoptosis and inhibited migration of the breast cancer cells. Moreover, the combination of ZA and PL decreased the expression of Notch-1, cleaved PARP, Bcl-2 and Bcl-xl, and increased the expression of cleaved caspase-3, CDKN1A and ID1. When the breast cancer cells were transfected with specific siRNA against Notch-1, the combination of ZA and PL markedly increased the expression of Bcl-2.

Conclusion: Combination of ZA and PL synergistically suppresses human breast cancer MDA-MB-231SArfp cells in vitro. PL can inhibit ZA-induced activation of the Notch-1 signaling pathway and subsequently reduce the expression of Bcl-2, thus potentiating cancer cell apoptosis.

No MeSH data available.


Related in: MedlinePlus