Planta Med 2013; 79 - PH4
DOI: 10.1055/s-0033-1352081

Identification of new pro-apoptotic inhibitors of HSP70

L Faiella 1, R Cotugno 2, D Gallotta 2, M Vasaturo 2, M Belisario 2, F Dal Piaz 2, M Bruno 3, A Braca 4, N De Tommasi 2
  • 1Dipartimento di Farmacia, Università di Pisa, 56126 Pisa, Italy
  • 2Dipartimento di Farmacia, Università di Salerno,84084 Fisciano (SA), Italy
  • 3Dipartimento Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, 90128 Palermo
  • 4Dipartimento di Farmacia, Università di Pisa,56126 Pisa Italy

Oridonin is a very promising anti-cancer ent-kaurane diterpene.1 – 4 Recently we have demonstrated that the pro-apoptotic activity of oridonin depends on its ability inhibit the activity of HSP70.5 It is a member of a ubiquitously expressed family of molecular chaperones involved in de novo protein folding, subcellular trafficking, proteasome-mediated degradation, and autophagy. At the initial stages of tumorigenesis, HSP70 has been shown to protect the cells undergoing transformation from oncogenic stress induced by overexpression of oncogenes. HSP70 over-expression has been routinely associated with poor prognosis in multiple forms of cancer and is thought to provide a survival advantage to cancer cells interacting with multiple cellular pathways.6

On the basis of this data we started a systematic study by surface plasmon resonance on diterpenes structurally related to oridonin in order to find out new HSP70 inhibitors. Our investigations demonstrated that 15-ketoatractyligenin methylester (SR2017), the semi-synthetic derivative of the nor-diterpene atractyligenin, binds with high affinity the chaperone. This interaction was also confirmed by chemical proteomics experiments performed on Jurkat cell protein extracts. We also demonstrated the ability of SR2017 to inhibit the growth of tumor-derived cell lines with higher potency than oridonin. Moreover, we found that this compound causes mainly cell cycle impairment, inducing cells to accumulate in S/G2-M, also leading to cell death by apoptosis. These results are in agreement with a possible inhibitory effect of SR2017 on HSP70 and suggest this compound as a new promising anti-cancer agent.

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