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Combinatorial antitumor effect of HDAC and the PI3K-Akt-mTOR pathway inhibition in a Pten defecient model of prostate cancer.

Ellis L, Ku SY, Ramakrishnan S, Lasorsa E, Azabdaftari G, Godoy A, Pili R - Oncotarget (2013)

Bottom Line: In this study we utilized the AR negative PCa cell line and observed that re-expression of AR (PC3-AR) results in greater levels of apoptosis when treated with the pan-DACi, panobinostat (PAN).Combination of PAN with BEZ235 resulted in significant attenuation of the DNA damage repair protein ATM and significantly increased anti-tumor activity compared to each single treatment.Overall, superior anti-tumor activity with combination of PAN with BEZ235 was independent of AR status.

View Article: PubMed Central - PubMed

Affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo NY.

ABSTRACT
Increased expression of histone deacetylases (HDACs) and activation of the PI3K-Akt-mTORC1 pathway are common aberrations in prostate cancer (PCa). For this reason, inhibition of such targets is an exciting avenue for the development of novel therapeutic strategies to treat patients with advanced PCa. Previous reports demonstrated that HDAC inhibitors (HDACi) increases DNA damage and induce greater apoptosis in PCa cell lines that express androgen receptor (AR). In this study we utilized the AR negative PCa cell line and observed that re-expression of AR (PC3-AR) results in greater levels of apoptosis when treated with the pan-DACi, panobinostat (PAN). PAN mediated apoptosis in PC3 and PC3-AR cells was associated with increased levels of double strand DNA breaks, indicated by p-ɣH2AX. Further, PAN treatment in PC3-AR cells resulted in moderate attenuation of the ATM-Akt-ERK DNA damage response pathway. For this reason, we combined PAN with the dual PI3K-mTOR inhibitor, BEZ235. Combination of PAN with BEZ235 resulted in significant attenuation of the DNA damage repair protein ATM and significantly increased anti-tumor activity compared to each single treatment. Overall, superior anti-tumor activity with combination of PAN with BEZ235 was independent of AR status. These findings suggest that this therapeutic strategy should be further developed in clinical trials.

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Related in: MedlinePlus

Schematic representation of activity of BEZ235/panobinostat combination against PC3 and PC3-AR tumor modelsCombination treatment of BEZ235 with panobinostat maintains/increases DNA double strand breaks as indicated by ɣ-H2AX. Further, combination treatment results in a superior suppression of the DNA damage response pathway mediated through ATM-Akt-Erk1/2. Overall, combination therapy creates an imbalance between DNA damage and DNA damage response generating greater therapeutic efficacy.
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Figure 7: Schematic representation of activity of BEZ235/panobinostat combination against PC3 and PC3-AR tumor modelsCombination treatment of BEZ235 with panobinostat maintains/increases DNA double strand breaks as indicated by ɣ-H2AX. Further, combination treatment results in a superior suppression of the DNA damage response pathway mediated through ATM-Akt-Erk1/2. Overall, combination therapy creates an imbalance between DNA damage and DNA damage response generating greater therapeutic efficacy.

Mentions: In conclusion, targeting advanced prostate cancer largely involves inhibitors towards androgen synthesis and androgen receptor transactivation. Together, our data provides rationale for the clinical translation of PAN combined with BEZ235 for treatment of advanced prostate cancer, independent of AR status. While targeting the DNA damage/DNA repair axis has been a goal of chemotherapy intervention, toxicity has made this strategy difficult to manage clinically. Both PAN and BEZ235 have returned favorable toxicity profiles in cancer patients and results from our study demonstrate that combination therapy sustains or increases intratumoral DNA damage while attenuating DNA damage repair (decreased ATM) and survival pathway (activated Akt and Erk1/2) signaling independent of AR status (Fig. 7). The optimal clinical setting to test this combination strategy remains to be determined but the molecular mechanism highlighted in this study suggests several potential rational combination strategies both pre and post docetaxel treatment. Overall, these data highlight the necessity of this therapeutic strategy to be further clinically developed to treat patients with advanced prostate cancer.


Combinatorial antitumor effect of HDAC and the PI3K-Akt-mTOR pathway inhibition in a Pten defecient model of prostate cancer.

Ellis L, Ku SY, Ramakrishnan S, Lasorsa E, Azabdaftari G, Godoy A, Pili R - Oncotarget (2013)

Schematic representation of activity of BEZ235/panobinostat combination against PC3 and PC3-AR tumor modelsCombination treatment of BEZ235 with panobinostat maintains/increases DNA double strand breaks as indicated by ɣ-H2AX. Further, combination treatment results in a superior suppression of the DNA damage response pathway mediated through ATM-Akt-Erk1/2. Overall, combination therapy creates an imbalance between DNA damage and DNA damage response generating greater therapeutic efficacy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926822&req=5

Figure 7: Schematic representation of activity of BEZ235/panobinostat combination against PC3 and PC3-AR tumor modelsCombination treatment of BEZ235 with panobinostat maintains/increases DNA double strand breaks as indicated by ɣ-H2AX. Further, combination treatment results in a superior suppression of the DNA damage response pathway mediated through ATM-Akt-Erk1/2. Overall, combination therapy creates an imbalance between DNA damage and DNA damage response generating greater therapeutic efficacy.
Mentions: In conclusion, targeting advanced prostate cancer largely involves inhibitors towards androgen synthesis and androgen receptor transactivation. Together, our data provides rationale for the clinical translation of PAN combined with BEZ235 for treatment of advanced prostate cancer, independent of AR status. While targeting the DNA damage/DNA repair axis has been a goal of chemotherapy intervention, toxicity has made this strategy difficult to manage clinically. Both PAN and BEZ235 have returned favorable toxicity profiles in cancer patients and results from our study demonstrate that combination therapy sustains or increases intratumoral DNA damage while attenuating DNA damage repair (decreased ATM) and survival pathway (activated Akt and Erk1/2) signaling independent of AR status (Fig. 7). The optimal clinical setting to test this combination strategy remains to be determined but the molecular mechanism highlighted in this study suggests several potential rational combination strategies both pre and post docetaxel treatment. Overall, these data highlight the necessity of this therapeutic strategy to be further clinically developed to treat patients with advanced prostate cancer.

Bottom Line: In this study we utilized the AR negative PCa cell line and observed that re-expression of AR (PC3-AR) results in greater levels of apoptosis when treated with the pan-DACi, panobinostat (PAN).Combination of PAN with BEZ235 resulted in significant attenuation of the DNA damage repair protein ATM and significantly increased anti-tumor activity compared to each single treatment.Overall, superior anti-tumor activity with combination of PAN with BEZ235 was independent of AR status.

View Article: PubMed Central - PubMed

Affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo NY.

ABSTRACT
Increased expression of histone deacetylases (HDACs) and activation of the PI3K-Akt-mTORC1 pathway are common aberrations in prostate cancer (PCa). For this reason, inhibition of such targets is an exciting avenue for the development of novel therapeutic strategies to treat patients with advanced PCa. Previous reports demonstrated that HDAC inhibitors (HDACi) increases DNA damage and induce greater apoptosis in PCa cell lines that express androgen receptor (AR). In this study we utilized the AR negative PCa cell line and observed that re-expression of AR (PC3-AR) results in greater levels of apoptosis when treated with the pan-DACi, panobinostat (PAN). PAN mediated apoptosis in PC3 and PC3-AR cells was associated with increased levels of double strand DNA breaks, indicated by p-ɣH2AX. Further, PAN treatment in PC3-AR cells resulted in moderate attenuation of the ATM-Akt-ERK DNA damage response pathway. For this reason, we combined PAN with the dual PI3K-mTOR inhibitor, BEZ235. Combination of PAN with BEZ235 resulted in significant attenuation of the DNA damage repair protein ATM and significantly increased anti-tumor activity compared to each single treatment. Overall, superior anti-tumor activity with combination of PAN with BEZ235 was independent of AR status. These findings suggest that this therapeutic strategy should be further developed in clinical trials.

Show MeSH
Related in: MedlinePlus