Oronsky Bryan, Reid Tony R, Oronsky Arnold, Caroen Scott, Carter Corey A, Cabrales Pedro
EpicentRx Inc, San Diego, CA 92121, USA.
Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Oncotarget. 2018 May 4;9(34):23439-23442. doi: 10.18632/oncotarget.25211.
The goal of anticancer therapy is to selectively eradicate all malignant cells. Unfortunately for the majority of patients with metastatic disease, this goal is consistently thwarted by the nearly inevitable development of therapeutic resistance; the main driver of therapeutic resistance is a minority subpopulation of cancer cells called cancer stem cells (CSCs) whose mitotic quiescence essentially renders them non-eradicable. The Wnt signaling pathway has been widely implicated as a regulator of CSCs and, therefore, its inhibition is thought to result in a reversal of therapeutic resistance via loss of stem cell properties. RRx-001 is a minimally toxic redox-active epi-immunotherapeutic anticancer agent in Phase III clinical trials that sensitizes tumors to radiation and cytotoxic chemotherapies. In this article, as a potential mechanism for its radio- and chemosensitizing activity, we report that RRx-001 targets CD133 /CD44 cancer stem cells from three colon cancer cell-lines, HT-29, Caco-2, and HCT116, and inhibits Wnt pathway signalling with downregulation of c-Myc.
抗癌治疗的目标是选择性地根除所有恶性细胞。不幸的是，对于大多数患有转移性疾病的患者来说，这一目标一直受到治疗耐药性几乎不可避免的发展的阻碍；治疗耐药性的主要驱动因素是一小部分癌细胞亚群，称为癌症干细胞（CSCs），其有丝分裂静止基本上使其无法根除。Wnt信号通路已被广泛认为是CSCs的调节剂，因此，其抑制被认为会通过干细胞特性的丧失导致治疗耐药性的逆转。RRx-001是一种毒性极小的氧化还原活性表位免疫治疗抗癌药物，正在进行III期临床试验，可使肿瘤对放疗和细胞毒性化疗敏感。在本文中，作为其放射增敏和化学增敏活性的潜在机制，我们报告RRx-001靶向来自三种结肠癌细胞系HT-29、Caco-2和HCT116的CD133/CD44癌症干细胞，并通过下调c-Myc抑制Wnt通路信号传导。
