Apoptosis

, Volume 22, Issue 11, pp 1394–1403 | Cite as

Novel histone deacetylase 8-selective inhibitor 1,3,4-oxadiazole-alanine hybrid induces apoptosis in breast cancer cells

  • Vijaya Rao Pidugu
  • Nagendra Sastry Yarla
  • Anupam Bishayee
  • Arunasree M. Kalle
  • Alapati Krishna Satya
Original Paper

Abstract

Identification of isoform-specific histone deacetylase inhibitors (HDACi) is a significant advantage to overcome the adverse side effects of pan-HDACi for the treatment of various diseases, including cancer. We have designed, and synthesized novel 1,3,4 oxadiazole with glycine/alanine hybrids as HDAC8-specific inhibitors and preliminary evaluation has indicated that 1,3,4 oxadiazole with alanine hybrid [(R)-2-amino-N-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)propanamide (10b)] to be a potent HDAC8 inhibitor. In the present study, the in vitro efficacy of the molecule in inhibiting the cancer cell proliferation and the underlying molecular mechanism was studied. 10b inhibited the growth of MDA-MB-231 and MCF7 breast cancer cells, with a lower IC50 of 230 and 1000 nM, respectively, compared to K562, COLO-205 and HepG2 cells and was not cytotoxic to normal breast epithelial cells, MCF10A. 10b was specific to HDAC8 and did not affect the expression of other class I HDACs. Further, a dose-dependent increase in H3K9 acetylation levels demonstrated the HDAC-inhibitory activity of 10b in MDA-MB-231 cells. Flow cytometric analysis indicated a dose-dependent increase and decrease in the percent apoptotic cells and mitochondrial membrane potential, respectively, when treated with 10b. Immunoblot analysis showed a modulation of Bax/Bcl2 ratio with a decrease in Bcl2 expression and no change in Bax expression. 10b treatment resulted in induction of p21 and inhibition of CDK1 proteins along with cytochrome c release from mitochondria, activation of caspases-3 and -9 and cleavage of poly ADP-ribose polymerase leading to apoptotic death of MDA-MB-231 and MCF7 cells. In conclusion, our results clearly demonstrated the efficacy of 10b as an anticancer agent against breast cancer.

Keywords

HDAC8-selective inhibitor 1,3,4 Oxadiazole-alanine hybrid Apoptosis Breast cancer cells 

Notes

Funding

The funding was provided by Department of Biotechnology, Ministry of Science and Technology (Grant No. BT/327/NE/TBP/2012) to AMK. ​NSY is thankful to Department of Science and Technology for financial support through N-PDF (SERB File Number: PDF/2016/003244).

Supplementary material

10495_2017_1410_MOESM1_ESM.pdf (631 kb)
Supplementary material 1 (PDF 630 KB)

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Vijaya Rao Pidugu
    • 1
    • 2
  • Nagendra Sastry Yarla
    • 3
    • 4
  • Anupam Bishayee
    • 5
  • Arunasree M. Kalle
    • 4
    • 6
  • Alapati Krishna Satya
    • 2
  1. 1.GVK Biosciences Private LimitedHyderabadIndia
  2. 2.Department of BiotechnologyAcharya Nagarjuna UniversityGunturIndia
  3. 3.Department of Biochemistry/Bioinformatics, Institute of ScienceGITAM UniversityVishakhapatnamIndia
  4. 4.Department of Animal Biology, School of Life SciencesUniversity of HyderabadHyderabadIndia
  5. 5.Department of Pharmaceutical Sciences, College of PharmacyLarkin UniversityMiamiUSA
  6. 6.Department of Environmental Health Sciences, Laboratory of Human Environmental Epigenomes, Bloomberg School of Public HealthJohns Hopkins UniversityBaltimoreUSA

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