Breast carcinoma is one of the most common malignancies in women. Previous studies have reported that 500 μM valproic acid can sensitize breast tumor cells to the anti-neoplastic agent hydroxyurea. However, the dose requirements for valproic acid is highly variable due to the wide inter-individuals clinical characteristics. High therapeutic dose of valproic acid required to induce anti-tumor activity in solid tumor was associated with increased adverse effects. There are attempts to locate suitably high-efficient low-toxicity valproic acid derivatives. We demonstrated that lower dose of 2-hexyl-4-pentynoic acid (HPTA; 15 μM) has similar effects as 500 μM VPA in inhibiting breast cancer cell growth and sensitizing the tumor cells to hydroxyurea on MCF7 cells, EUFA423 cells, MCF7 cells with defective RPA2-p gene and primary culture cells derived from tissue-transformed breast tumor cells. We discovered HPTA resulted in more DNA double-strand breaks, the homologous recombination was inhibited through the interference of the hyperphosphorylation of replication protein A2 and recombinase Rad51. Our data postulate that HPTA may be a potential novel sensitizer to hydroxyurea in the treatment of breast carcinoma.

乳腺癌是女性中最常见的恶性肿瘤之一。先前的研究报道，500μM丙戊酸可使乳腺肿瘤细胞对抗肿瘤药羟基脲敏感。然而，由于广泛的个体间临床特征，丙戊酸的剂量要求变化很大。在实体瘤中诱导抗肿瘤活性所需的高剂量丙戊酸与不良反应增加有关。尝试找到合适的高效低毒丙戊酸衍生物。我们证明了较低剂量的2-己基-4-戊酸（HPTA; 15μM）在抑制乳腺癌细胞生长并使MCF7细胞，EUFA423细胞对肿瘤细胞产生羟基脲敏感性方面具有与500μMVPA类似的作用，RPA2-p基因缺陷的MCF7细胞和源自组织转化的乳腺肿瘤细胞的原代培养细胞。我们发现HPTA导致更多的DNA双链断裂，通过复制蛋白A2和重组酶Rad51的过度磷酸化的干扰抑制了同源重组。我们的数据假设HPTA可能是治疗乳腺癌中对羟基脲的潜在新型敏化剂。