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Inhibition of androgen-independent prostate cancer cell growth is enhanced by combination therapy targeting Hedgehog and ErbB signalling.

Shaw G, Prowse DM - Cancer Cell Int. (2008)

Bottom Line: Synergistic antiproliferation effects were observed when the Hedgehog and ErbB inhibitors were combined.Cyclopamine, gefitinib or lapatinib treatment significantly decreased the proliferation of androgen-independent prostate cancer cells.Synergistic effects were observed when Hedgehog and ErbB inhibitors were used together.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Cancer, Bart's and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK. gregshaw1@gmail.com

ABSTRACT

Background: Prostate cancer is a leading cause of male cancer specific mortality. When cure by radical prostatectomy is not possible the next line of prostate cancer treatment is androgen deprivation. However prolonged androgen deprivation often results in relapse and androgen-independent prostate cancer that is inevitably fatal despite optimal chemotherapy. The Hedgehog signalling pathway has recently been implicated in prostate cancer development and metastasis. EGFR or ErbB2 expression has been also correlated with androgen independence, shorter survival and metastasis.

Results: We determined that the Hedgehog and ErbB signalling pathways are active in circulating tumour cells isolated from androgen-independent prostate cancer patients and in the androgen-independent prostate cancer cell line LNCaP C4-2B. As a basis for synergistic chemotherapy protocols combinations of the Hedgehog specific inhibitor cyclopamine and the ErbB signalling inhibitors gefitinib or lapatinib were tested in this study. Androgen-independent prostate cancer cell growth was inhibited by a SMO inhibitor (cyclopamine) which blocks Hedgehog signalling and by ErbB inhibitors (gefitinib and lapatinib). The isobologram and combination index method of Chou and Talalay was used to evaluate drug interactions. Synergistic antiproliferation effects were observed when the Hedgehog and ErbB inhibitors were combined.

Conclusion: Androgen-independent prostate cancer cell proliferation was associated with activity of the Hedgehog and ErbB signalling pathways. Cyclopamine, gefitinib or lapatinib treatment significantly decreased the proliferation of androgen-independent prostate cancer cells. The Hedgehog pathway therefore represents a promising new therapeutic target in androgen-independent prostate cancer. Synergistic effects were observed when Hedgehog and ErbB inhibitors were used together. This study may have clinical implications for improving the treatment of advanced prostate cancer.

No MeSH data available.


Related in: MedlinePlus

Analysis of cyclopamine and (A-B) gefitinib or (C-D) lapatinib in LNCaP C4-2B cells. (A and C) combination index plot for the drug combinations. (B and D) Isobologram for the combination of gefitinib or (C-D) lapatinib and cyclopamine for effect level (Fa = 0.5). Note the combination data points fall on the lower left of the hypotenuse for Fa = 0.5 (shown), Fa = 0.75 and Fa = 0.9 indicating synergism.
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Figure 6: Analysis of cyclopamine and (A-B) gefitinib or (C-D) lapatinib in LNCaP C4-2B cells. (A and C) combination index plot for the drug combinations. (B and D) Isobologram for the combination of gefitinib or (C-D) lapatinib and cyclopamine for effect level (Fa = 0.5). Note the combination data points fall on the lower left of the hypotenuse for Fa = 0.5 (shown), Fa = 0.75 and Fa = 0.9 indicating synergism.

Mentions: In order to establish whether the combined effects of Hedgehog and ErbB inhibitors were synergistic the isobologram and combination index (CI) was calculated according to the Chou and Talalay median effect principal [24]. Inhibitors were applied to androgen-independent LNCaP C4-2B cells at concentrations relative to their respective IC50 values keeping the ratio of one drug to the other constant. For each drug combination the MTT assays were carried out in three separate experiments and the relative growth rates calculated in comparison with LNCaP C4-2B cells cultured in androgen free medium in the absence of any cytotoxic drugs. The Hedgehog inhibitor cyclopamine as single agent or in combination with the ErbB inhibitors gefitinib or lapatinib inhibited the growth of LNCaP C4-2B cells. Figure 5A shows the dose response curve for cyclopamine and gefitinib applied alone and in combination and Figure 5B shows the dose response curve for cyclopamine and lapatinib applied alone and in combination. Figure 6 shows the combination effect plots and isobolograms for the inhibitor combinations. Table 1 shows the combination index for treating androgen-independent LNCaP C4-2B cells with inhibitor combinations, with values below 0.9 indicating synergism and above 1.1 antagonism. Strong synergistic effects resulted from the combination of cyclopamine with gefitinib or lapatinib.


Inhibition of androgen-independent prostate cancer cell growth is enhanced by combination therapy targeting Hedgehog and ErbB signalling.

Shaw G, Prowse DM - Cancer Cell Int. (2008)

Analysis of cyclopamine and (A-B) gefitinib or (C-D) lapatinib in LNCaP C4-2B cells. (A and C) combination index plot for the drug combinations. (B and D) Isobologram for the combination of gefitinib or (C-D) lapatinib and cyclopamine for effect level (Fa = 0.5). Note the combination data points fall on the lower left of the hypotenuse for Fa = 0.5 (shown), Fa = 0.75 and Fa = 0.9 indicating synergism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2311276&req=5

Figure 6: Analysis of cyclopamine and (A-B) gefitinib or (C-D) lapatinib in LNCaP C4-2B cells. (A and C) combination index plot for the drug combinations. (B and D) Isobologram for the combination of gefitinib or (C-D) lapatinib and cyclopamine for effect level (Fa = 0.5). Note the combination data points fall on the lower left of the hypotenuse for Fa = 0.5 (shown), Fa = 0.75 and Fa = 0.9 indicating synergism.
Mentions: In order to establish whether the combined effects of Hedgehog and ErbB inhibitors were synergistic the isobologram and combination index (CI) was calculated according to the Chou and Talalay median effect principal [24]. Inhibitors were applied to androgen-independent LNCaP C4-2B cells at concentrations relative to their respective IC50 values keeping the ratio of one drug to the other constant. For each drug combination the MTT assays were carried out in three separate experiments and the relative growth rates calculated in comparison with LNCaP C4-2B cells cultured in androgen free medium in the absence of any cytotoxic drugs. The Hedgehog inhibitor cyclopamine as single agent or in combination with the ErbB inhibitors gefitinib or lapatinib inhibited the growth of LNCaP C4-2B cells. Figure 5A shows the dose response curve for cyclopamine and gefitinib applied alone and in combination and Figure 5B shows the dose response curve for cyclopamine and lapatinib applied alone and in combination. Figure 6 shows the combination effect plots and isobolograms for the inhibitor combinations. Table 1 shows the combination index for treating androgen-independent LNCaP C4-2B cells with inhibitor combinations, with values below 0.9 indicating synergism and above 1.1 antagonism. Strong synergistic effects resulted from the combination of cyclopamine with gefitinib or lapatinib.

Bottom Line: Synergistic antiproliferation effects were observed when the Hedgehog and ErbB inhibitors were combined.Cyclopamine, gefitinib or lapatinib treatment significantly decreased the proliferation of androgen-independent prostate cancer cells.Synergistic effects were observed when Hedgehog and ErbB inhibitors were used together.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Cancer, Bart's and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK. gregshaw1@gmail.com

ABSTRACT

Background: Prostate cancer is a leading cause of male cancer specific mortality. When cure by radical prostatectomy is not possible the next line of prostate cancer treatment is androgen deprivation. However prolonged androgen deprivation often results in relapse and androgen-independent prostate cancer that is inevitably fatal despite optimal chemotherapy. The Hedgehog signalling pathway has recently been implicated in prostate cancer development and metastasis. EGFR or ErbB2 expression has been also correlated with androgen independence, shorter survival and metastasis.

Results: We determined that the Hedgehog and ErbB signalling pathways are active in circulating tumour cells isolated from androgen-independent prostate cancer patients and in the androgen-independent prostate cancer cell line LNCaP C4-2B. As a basis for synergistic chemotherapy protocols combinations of the Hedgehog specific inhibitor cyclopamine and the ErbB signalling inhibitors gefitinib or lapatinib were tested in this study. Androgen-independent prostate cancer cell growth was inhibited by a SMO inhibitor (cyclopamine) which blocks Hedgehog signalling and by ErbB inhibitors (gefitinib and lapatinib). The isobologram and combination index method of Chou and Talalay was used to evaluate drug interactions. Synergistic antiproliferation effects were observed when the Hedgehog and ErbB inhibitors were combined.

Conclusion: Androgen-independent prostate cancer cell proliferation was associated with activity of the Hedgehog and ErbB signalling pathways. Cyclopamine, gefitinib or lapatinib treatment significantly decreased the proliferation of androgen-independent prostate cancer cells. The Hedgehog pathway therefore represents a promising new therapeutic target in androgen-independent prostate cancer. Synergistic effects were observed when Hedgehog and ErbB inhibitors were used together. This study may have clinical implications for improving the treatment of advanced prostate cancer.

No MeSH data available.


Related in: MedlinePlus