Figure 4. Tankyrase inhibitor enhances the growth inhibitory effects of DNA-damaging anticancer drugs.

(A) A549 cells were treated with DNA-damaging anticancer drugs (bleomycin, doxorubicin, cisplatin, etoposide and camptothecin) at various concentrations in the presence or absence of 3 μM G007-LK or olaparib. After a 10-day cultivation, colonies were quantitated and normalized with the colony numbers from cells treated with either DMSO, G007-LK or olaparib alone, in which cell viability was defined as 100%. Three independent experiments were performed and each experiment was performed in triplicate. (B) The IC₅₀ values of each drug treatment in A is shown in the table. The ratios of IC₅₀ values in the combination treatment of DNA-damaging anticancer drugs with G007-LK or olaparib compared with the anticancer drugs with DMSO are shown in the right column. (C) A schematic model of potentiated sensitivity to DNA damage by tankyrase inhibition. Left: when DNA double-strand break (DSB) is created by X-ray or anticancer drugs, tankyrase forms a complex with MERIT40-BRE-BRCC36 through direct association with MERIT40. Then, tankyrase-mediated PARsylation plays a role to facilitate the DNA repair process. Right: inhibition of either tankyrase-MERIT40 association or tankyrase PARP activity causes dysfunction in DNA repair process, resulting in deleterious effects, such as cell death.