Geron Corp (GERN)

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Inhibiting hTERT 2

Our data suggest that inhibition of hTERT expression by siRNA may constitute a valid strategy of chemosensitization. Future investigation will reveal whether hTERT-specific siRNAs with improved in vivo pharmacokinetics may enter the clinics. Intriguingly, there are a number of drugs used in experimental chemotherapy that are able to downmodulate hTERT expression at the mRNA or protein levels. This applies to rapamycin (Zhou et al., 2003), histone deacetylase inhibitors (Wu et al., 2005), imatinib mesylate (Gleevec) (Uziel et al., 2005), the Bcl-2/Bcl-XL-specific antisense oligonucleotide 4625 (Del Bufalo et al., 2005), as well as vitamin D3 (Jiang et al., 2004). It remains to be determined, however, to which extent hTERT downmodulation may explain the cytotoxic and chemosensitizing effects of such drugs.

Irrespective of these incognita, it appears that hTERT may constitute an ideal target for a double-hit anticancer strategy. Whereas inhibition of the catalytic telomerase activity should limit the lifespan of tumor cells and hence exert a long-term effect obtained by chronic therapy, acute inhibition of the second antiapoptotic function can yield an immediate chemosensitizing effect, including in tumors in which the p53 pathway is subverted. However, tumors in which the Bax-dependent mitochondrial pathway of apoptosis induction has been invalidated by loss of expression of Bax or overexpression of Bcl-2 are refractory to chemosensitization by hTERT inhibition.

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