Wang Yangyang, Li Wende, Patel Shalin S, Cong Juan, Zhang Nan, Sabbatino Francesco, Liu Xiaoyan, Qi Yuan, Huang Peigen, Lee Hang, Taghian Alphonse, Li Jian-Jian, DeLeo Albert B, Ferrone Soldano, Epperly Michael W, Ferrone Cristina R, Ly Amy, Brachtel Elena F, Wang Xinhui
Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA.
Oncotarget. 2014 Jun 15;5(11):3743-55. doi: 10.18632/oncotarget.1992.
The goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu2+). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu2+ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer.
乳腺癌辅助（术后）放射治疗（RT）的目标是消除残留癌细胞，实现更好的局部肿瘤控制，从而提高患者生存率。然而，放射抗性会增加肿瘤复发风险并对生存率产生负面影响。最近的证据表明，乳腺癌干细胞（BCSCs）具有放射抗性，并且相对分化的乳腺癌细胞可通过辐射诱导干性基因的重新表达重编程为诱导性乳腺癌干细胞（iBCSCs）。在此我们表明，在接受照射（IR）的同基因乳腺肿瘤小鼠中，IR诱导的干性与自发性肺转移增加相关（51.7%）。然而，通过用双硫仑（DSF）和铜（Cu2+）靶向NF-κB-干性基因途径可阻断IR诱导的干性。DSF是醛脱氢酶（ALDH）的抑制剂，也是一种经美国食品药品监督管理局（FDA）批准用于治疗酒精中毒的药物。DSF与Cu2+结合形成DSF-Cu复合物（DSF/Cu），其作为一种有效的凋亡诱导剂和蛋白酶体抑制剂，进而抑制NF-κB激活。与用赋形剂处理的小鼠相比，用RT和DSF处理小鼠可显著抑制乳腺原发性肿瘤生长（79.4%）和自发性肺转移（89.6%）。这种抗肿瘤功效与肿瘤中干细胞特性（或干性）降低有关。我们期望这些结果将引发对RT和DSF作为乳腺癌新型联合治疗方法的临床研究。
