Visit HSP90 Central for a number of abstracts related to their HSP90 inhibitor ganetespib (STA-9090)
Abstract Number: 1757
Elesclomol (STA-4783) is a potent inhibitor of topoisomerase II
Elesclomol (STA-4783; N'1,N'3-dimethyl-N'1,N'3- bis(phenylcarbonothioyl)propanedihydrazide) is an anticancer drug that has received both fast track and orphan drug status from the FDA and is currently undergoing clinical trials. Elesclomol forms a strong 1:1 complex with copper(II) and may exert its anticancer activity through the induction of oxidative stress. In the studies reported here elesclomol was assessed for its ability to inhibit: 1) the growth of the human erythroleukemic K562 cell line and an etoposide-resistant K/VP.5 cell line; 2) the decatenation activity of DNA topoisomerase IIα; and 3) the relaxation activity of DNA topoisomerase I. Elesclomol was also evaluated for its ability to induce topoisomerase IIα-mediated double strand cleavage of pBR322 DNA and to form topoisomerase IIα-DNA covalent adducts in the cell-based ICE assay. Elesclomol inhibited K562 cell growth in the submicromolar concentration range. However, K/VP.5 cells were not cross-resistant. Elesclomol also strongly inhibited the decatenation activity of topoisomerase IIα in the low micromolar concentration range. Elesclomol may also act as topoisomerase IIα poison because it induced formation of linear DNA, though not as strongly as etoposide. In conclusion, these results show that elesclomol may, in part, inhibit cell growth through the targeting of topoisomerase II.
Abstract Number: 1761
Breast cancers with compromised DNA repair exhibit selective sensitivity to elesclomol-induced oxidative DNA damage
Hereditary breast cancers due to germline mutations in BRCA1 and sporadic breast cancers of the basal-like subtype are often triple-negative, i.e. lack expression of estrogen and progesterone receptors and lack overexpression/amplification of the HER2/neu oncogene. Given that the triple-negative status of these cancers renders them relatively insensitive to existing “targeted” therapy, improved treatment options are needed. We tested a panel of cell lines that represent the different molecular subtypes of breast cancer for sensitivity to elesclomol, an experimental therapeutic that produces elevated levels of oxidative DNA damage, using the MTT assay. We found that both BRCA1-mutated and basal-like breast cancer cell lines with defective base-excision DNA repair (BER) were markedly more sensitive to elesclomol than cell lines that represent the normal breast or other subtypes of breast cancer with proficient BER. We also assessed sensitivity to elesclomol in breast cancer cell lines that were stably transduced with shRNA to OGG1, a BER glycosylase required for the repair of the most common type of oxidative DNA damage. Two different cell lines with decreased levels of OGG1 (shOGG1A, 50% knock-down; shOGG1B, 20% knock-down) were more sensitive to elesclomol (IC50 = 0.04nM and 0.3nM, respectively) compared to two different isogenic control cell lines (IC50 = 2nM and 3nM, respectively). Taken together, these data suggest that compromised repair of oxidative DNA damage by BER represents a functional target for elesclomol. Overall, BRCA1-mutated and/or basal-like breast cancers may benefit from treatment regimens that include elesclomol.