SIRT proteins play an important role in the survival and drug resistance of tumour
cells, especially during chemotherapy. In this study, we investigated the potency,
specificity and cellular targets of three recently identified SIRT inhibitors, Sirtinol,
Salermide and EX527. Our results identify the specificity and cellular targets of
these novel inhibitors, and suggest that SIRT inhibitors require combined
targeting of both SIRT1 and SIRT2 to induce p53 acetylation and cell death in
breast cancer cells. Assessing the role of sirtuins in chemoresistance, cisplatin
resistant cell lines were developed and characterized. Cisplatin resistant cells
(CisR) were found to have higher levels of SIRT1, repressing the activation of
FOXO3a. MCF-7 cells overexpressing SIRT1 were also shown to be protected
against cisplatin treatment, highlighting its role in resistance.
Sirtuins have many cellular targets, including alpha-tubulin, PARP, ku70 and
FOXO3a. Because of the similarities between the regulation of p53 and
FOXO3a, we decided to elucidate the effect of sirtinol treatment on FOXO3a.
Sirtinol treatment was shown to stabilize FOXO3a, similar to its effect on p53, but
at lower concentrations. We have shown previously that FOXO3a is an important
downstream mediator of the cytotoxicity of receptor tyrosine kinase targeted
therapies. To examine the conjecture whether sirtuin inhibitors could increase the
proapoptotic potency of lapatinib through stabilization of FOXO3a, lapatinib was
treated alone and in combination with sirtinol and EX527. Sirtinol was found to
synergise with lapatinib treatment (in cells containing mutant p53) and this was
dependent on the presence of FOXO proteins, highlighting the use of sirtuin
inhibitors in increasing the efficacy of therapies that indirectly target FOXO3a.