Limits...
Embelin, a small molecule quinone with a co-clinical power for castrate-resistant prostate cancer.

Poojari RJ - Front Pharmacol (2014)

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay Mumbai, India.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

As truly said, “Prevention is better than cure” we look forward for tailoring new treatment paradigms for the prevention of castration-resistant prostate cancers (CRPC)... Developing new, effective treatments and understanding the genetic catastrophes behind CRPCs is very challenging... Lunardi and team from Beth Israel Deaconess Medical Center, Harvard Medical School and other institutes unveiled how a co-clinical strategy comprising of a naturally occurring hydroxybenzoquinone, Embelin which is a small molecule X-linked inhibitor of apoptosis (XIAP), in dual/triple combinations with MDV3100 an androgen receptor (AR) antagonist, Bicalutamide an antiandrogen (Casodex) or Dutasteride a SRD5A1 (encoding 3-oxo-5-α-steroid 4-dehydrogenase 1) inhibitor and ADT currently in clinical trials are the targets for CRPC (Lunardi et al., )... They conducted an array-based comparative genomic hybridization which revealed the concomitant genetic loss and mutation of PTEN and ZBTB7A and TP53 stratifies with poor responsiveness to castration... The gene expression arrays suggested downregulation of XAF1 (X-linked inhibitor of apoptosis protein–associated factor-1), upregulation of SRD5A1, relocalization of AR to the nucleus and metastasis lead to poor sensitivity to ADT... The genetic make-up revealed the road-map of a powerful triple combination therapeutic strategy to CRPC patients genetically stratified by XAF1, XIAP, and SRD5A1... Triple treatment combinations with Bicalutamide (10 mg/kg), Embelin (60 mg/kg) oral dose for 3 days per week, Bicalutamide (10 mg/kg) and Dutasteride (2 mg/kg) oral dose 2 days per week for four weeks were also conducted... Embelin sensitized the CRPCs to ADT via XAF1-XIAP pathway, exhibited marked tumor regression and potent reduction in the proliferation rate when treated in combination with Bicalutamide in both PTEN and ZBTB7A genotypes in CRPCs... Embelin in combination with steroid-free medium and MDV3100 triggered the apoptosis promotion... Also, double for PTEN and ZBTB7A, for PTEN and TP53 as well as PTEN- CRPCs with SRD5A1 upregulation and, particularly the tricombo power of Dutasteride further significantly decreased the prostate tumor burden in response to Embelin treatment and ADT (Lunardi et al., )... The abrogation of the XAF1/XIAP pathway combined with SRD5A1 inhibition and ADT, implicates this new signature in designing and promotion of a natural plant based drug-targeting therapeutics on genetic mutations-driving biomarkers for the treatment of CRPC... The power of genomic triad with a co-clinical strategy would revolutionalize into translational human cancer therapy paving the way for similar approaches to other cancers too... The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

No MeSH data available.


Related in: MedlinePlus

A genomic triad with a co-clinical strategy targets for castrate-resistant prostate cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4126039&req=5

Figure 1: A genomic triad with a co-clinical strategy targets for castrate-resistant prostate cancer.

Mentions: Developing new, effective treatments and understanding the genetic catastrophes behind CRPCs is very challenging. Lunardi and team from Beth Israel Deaconess Medical Center, Harvard Medical School and other institutes unveiled how a co-clinical strategy comprising of a naturally occurring hydroxybenzoquinone, Embelin which is a small molecule X-linked inhibitor of apoptosis (XIAP), in dual/triple combinations with MDV3100 an androgen receptor (AR) antagonist, Bicalutamide an antiandrogen (Casodex) or Dutasteride a SRD5A1 (encoding 3-oxo-5-α-steroid 4-dehydrogenase 1) inhibitor and ADT currently in clinical trials are the targets for CRPC (Lunardi et al., 2013). Prostate cancers are characterized by distinct genetic backgrounds which respond differentially to ADT in mice and humans (Taylor et al., 2010). Moving closer to find important answers Lunardi et al. developed an integrated human-mouse cross-species genetic screening system which lead to identification of the key molecular pathways and genetic alterations in response to the standard therapeutics and new biomarkers. They conducted an array-based comparative genomic hybridization which revealed the concomitant genetic loss and mutation of PTEN and ZBTB7A and TP53 stratifies with poor responsiveness to castration. The gene expression arrays suggested downregulation of XAF1 (X-linked inhibitor of apoptosis protein–associated factor-1), upregulation of SRD5A1, relocalization of AR to the nucleus and metastasis lead to poor sensitivity to ADT. The genetic make-up revealed the road-map of a powerful triple combination therapeutic strategy to CRPC patients genetically stratified by XAF1, XIAP, and SRD5A1. The so-called genomic triad with a co-clinical strategy is justified (Figure 1).


Embelin, a small molecule quinone with a co-clinical power for castrate-resistant prostate cancer.

Poojari RJ - Front Pharmacol (2014)

A genomic triad with a co-clinical strategy targets for castrate-resistant prostate cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126039&req=5

Figure 1: A genomic triad with a co-clinical strategy targets for castrate-resistant prostate cancer.
Mentions: Developing new, effective treatments and understanding the genetic catastrophes behind CRPCs is very challenging. Lunardi and team from Beth Israel Deaconess Medical Center, Harvard Medical School and other institutes unveiled how a co-clinical strategy comprising of a naturally occurring hydroxybenzoquinone, Embelin which is a small molecule X-linked inhibitor of apoptosis (XIAP), in dual/triple combinations with MDV3100 an androgen receptor (AR) antagonist, Bicalutamide an antiandrogen (Casodex) or Dutasteride a SRD5A1 (encoding 3-oxo-5-α-steroid 4-dehydrogenase 1) inhibitor and ADT currently in clinical trials are the targets for CRPC (Lunardi et al., 2013). Prostate cancers are characterized by distinct genetic backgrounds which respond differentially to ADT in mice and humans (Taylor et al., 2010). Moving closer to find important answers Lunardi et al. developed an integrated human-mouse cross-species genetic screening system which lead to identification of the key molecular pathways and genetic alterations in response to the standard therapeutics and new biomarkers. They conducted an array-based comparative genomic hybridization which revealed the concomitant genetic loss and mutation of PTEN and ZBTB7A and TP53 stratifies with poor responsiveness to castration. The gene expression arrays suggested downregulation of XAF1 (X-linked inhibitor of apoptosis protein–associated factor-1), upregulation of SRD5A1, relocalization of AR to the nucleus and metastasis lead to poor sensitivity to ADT. The genetic make-up revealed the road-map of a powerful triple combination therapeutic strategy to CRPC patients genetically stratified by XAF1, XIAP, and SRD5A1. The so-called genomic triad with a co-clinical strategy is justified (Figure 1).

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay Mumbai, India.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

As truly said, “Prevention is better than cure” we look forward for tailoring new treatment paradigms for the prevention of castration-resistant prostate cancers (CRPC)... Developing new, effective treatments and understanding the genetic catastrophes behind CRPCs is very challenging... Lunardi and team from Beth Israel Deaconess Medical Center, Harvard Medical School and other institutes unveiled how a co-clinical strategy comprising of a naturally occurring hydroxybenzoquinone, Embelin which is a small molecule X-linked inhibitor of apoptosis (XIAP), in dual/triple combinations with MDV3100 an androgen receptor (AR) antagonist, Bicalutamide an antiandrogen (Casodex) or Dutasteride a SRD5A1 (encoding 3-oxo-5-α-steroid 4-dehydrogenase 1) inhibitor and ADT currently in clinical trials are the targets for CRPC (Lunardi et al., )... They conducted an array-based comparative genomic hybridization which revealed the concomitant genetic loss and mutation of PTEN and ZBTB7A and TP53 stratifies with poor responsiveness to castration... The gene expression arrays suggested downregulation of XAF1 (X-linked inhibitor of apoptosis protein–associated factor-1), upregulation of SRD5A1, relocalization of AR to the nucleus and metastasis lead to poor sensitivity to ADT... The genetic make-up revealed the road-map of a powerful triple combination therapeutic strategy to CRPC patients genetically stratified by XAF1, XIAP, and SRD5A1... Triple treatment combinations with Bicalutamide (10 mg/kg), Embelin (60 mg/kg) oral dose for 3 days per week, Bicalutamide (10 mg/kg) and Dutasteride (2 mg/kg) oral dose 2 days per week for four weeks were also conducted... Embelin sensitized the CRPCs to ADT via XAF1-XIAP pathway, exhibited marked tumor regression and potent reduction in the proliferation rate when treated in combination with Bicalutamide in both PTEN and ZBTB7A genotypes in CRPCs... Embelin in combination with steroid-free medium and MDV3100 triggered the apoptosis promotion... Also, double for PTEN and ZBTB7A, for PTEN and TP53 as well as PTEN- CRPCs with SRD5A1 upregulation and, particularly the tricombo power of Dutasteride further significantly decreased the prostate tumor burden in response to Embelin treatment and ADT (Lunardi et al., )... The abrogation of the XAF1/XIAP pathway combined with SRD5A1 inhibition and ADT, implicates this new signature in designing and promotion of a natural plant based drug-targeting therapeutics on genetic mutations-driving biomarkers for the treatment of CRPC... The power of genomic triad with a co-clinical strategy would revolutionalize into translational human cancer therapy paving the way for similar approaches to other cancers too... The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

No MeSH data available.


Related in: MedlinePlus