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Case Study 9 Role of HDACs in Neoplasms and use
of their inhibitors for cancer treatment
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Purpose of the Study

• Histone deacetylases (HDACs) are involved in
  increasing the positive charges of histones by
  removing the acetyl groups from histone
  proteins, initiating high affinity with DNA, thus
  preventing gene expression.
• Altered expression and mutations of genes that
  encode HDACs have been linked to tumor
  development since they both induce the aberrant
  transcription of key genes regulating important
  cellular functions such as cell proliferation,
  cell-cycle regulation and apoptosis.
• Purpose To find out the frequently occurring
  neoplasms associated with HDAC altered
  expression, drugs being used as HDAC inhibitors,
  and the processes encompassed by drugs to inhibit
  HDAC.

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Neoplasms Associated with HDACs

• One of the frequently occurring neoplasm
  associated with
• HDAC1 is Renal Cell Carcinoma (RCC).
• XTractor Facts
• Class I histone deacetylases 1, 2 and 3 are
  highly expressed in renal cell carcinoma .
• CONCLUSIONS Class I HDAC isoforms 1 and 2 are
  highly expressed in renal cell cancer , while
  HDAC 3 shows low, histology dependent expression
  rates.
• RESULTS Almost 60 of renal cell carcinomas
  expressed the HDAC isoforms 1 and 2.

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HDAC inhibitors

• The most frequently occurring HDAC inhibitor used
  against RCC is Valproic acid(VPA).
• XTractor Facts
• VPA significantly and dose-dependently
  up-regulated histone H3 and H4 acetylation and
  caused growth arrest in RCC cells.
• THE HISTONE DEACETYLASE INHIBITOR VALPROIC ACID
  ALTERS GROWTH PROPERTIES OF RENAL CELL CARCINOMA
  IN VITRO AND IN VIVO.

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Other drugs targeting HDAC in RCC Combination of
VPA with IFNA

• XTractor Facts
• VPA-IFNa combination markedly enhanced the
  effects of VPA on RCC adhesion, and in vivo tumor
  growth was further reduced by the 400 mg/kg but
  not by the 200 mg/kg VPA dosing schedule.
• VPA-IFNa combination markedly enhanced the
  effects of VPA monotherapy on RCC proliferation
  in vitro, but did not further enhance the
  anti-tumoural potential of VPA in vivo.

Reduction in RCC tumor growth was found to be
specific at 400 mg/kg but not by the 200 mg/kg
VPA dosing schedule
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Processes mediated by HDAC in causing neoplasm

• XTractor Facts
• Histone deacetylase inhibitors induce growth
  arrest, apoptosis, and differentiation in clear
  cell sarcoma models.
• Ribosome-inactivating proteins isolated from
  dietary bitter melon induce apoptosis and inhibit
  histone deacetylase-1 selectively in premalignant
  and malignant prostate cancer cells.
• Furthermore, depletion of HDAC2 but not HDAC1 or
  HDAC6 was sufficient to sensitize breast cancer
  cells to topoisomerase inhibitor-induced
  apoptosis.
• A novel delta-lactam-based histone deacetylase
  inhibitor, KBH-A42, induces cell cycle arrest and
  apoptosis in colon cancer cells.

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Other protein families associated with HDAC

• XTractor Facts
• PROTEIN KINASES
• AKT3_HUMAN, AURKB_HUMAN, AURKC_HUMAN,
  CD5R1_HUMAN , AKT1_HUMAN, AKT2_HUMAN, AKT3_HUMAN,
• BRAF1_HUMAN,FRAP_HUMAN, GRK5_HUMAN,
  MP2K1_HUMAN, MP2K2_HUMAN, MP2K3_HUMAN,MP2K4_HUMAN,
  
• MP2K5_HUMAN, MP2K6_HUMAN 
• HISTONES
• H10_HUMAN, H1FOO_HUMAN, H1X_HUMAN,H2AV_HUMAN
  ,H2AX_HUMAN, H2AY_HUMAN, H2AW_HUMAN,
• H2AZ_HUMAN, H2BFS_HUMAN,H2BWT_HUMAN,
  H33_HUMAN, H11_HUMAN, H15_HUMAN,
  H12_HUMAN,H13_HUMAN,
• H14_HUMAN, H1T_HUMAN, H2A1A_HUMAN,H2A1B_HUMAN
  ,H2A1C_HUMAN
• TYPE 1 GPCRs
• GRK5_HUMAN, GRPR_HUMAN
• TYPE 3 GPCRs

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Other Neoplasms associated with HDAC altered
expression

• XTractor Facts

• Breast Neoplasm, Pancreatic neoplasm, Prostatic
  Neoplasm,Rhabdoid Tumor,
• Colonic Neoplasms, Carcinoma, Non-Small-Cell
  Lung, Ovarian
• Neoplasms, Stomach Neoplasms, Neoplasms,
  Glandular and Epithelial, Lung
• Neoplasms,Lymphoma, T-Cell, Carcinoma, Renal Cell
  
• Leukemia, Myeloid, Acute,Neuroblastoma,
  Retinoblastoma

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The Final Analysis
Valproic acid
Breast Neoplasm, Pancreatic neoplasm, Prostatic
Neoplasm Carcinoma, Non-Small-Cell-Lung, Rhabdoid
Tumor, Colonic Neoplasms, Ovarian Neoplasms,
Stomach Neoplasms Neoplasms,Glandular and
Epithelial,Lung Neoplasms,Lymphoma,T-Cell,Carcinom
a, Renal Cell, Leukemia, Myeloid, Acute,
Neuroblastoma Retinoblastoma.
estrogen secretion
HDACs
Renal cell carcinoma
Protein kinases Type 1 GPCRs Type 3
GPCRs Histones Serine threonine phosphatases
Apoptosis Cell proliferation Growth
arrest Histone modification Histone acetylation
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• Toxicity
• Clearance
• Dosing
• Target prioritization
• Off target effects
• Drug reusability studies
• Mutation/SNP analysis
• Pathway studies
• Disease mechanisms

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• The One stop solution for all your drug discovery
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