Targeting nodal in conjunction with dacarbazine induces synergistic anticancer effects in metastatic melanoma.
Targeting nodal in conjunction with dacarbazine induces synergistic anticancer effects in metastatic melanoma.
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DOI：
10.1158/1541-7786.mcr-14-0077
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Hendrix MJ
中科院分区：
文献类型：
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作者：
Hardy KM;Strizzi L;Margaryan NV;Gupta K;Murphy GF;Scolyer RA;Hendrix MJ
转移性黑色素瘤是一种高度侵袭性的皮肤癌，预后不良。尽管在不到5%的患者中完全缓解，化疗药物达卡巴嗪（DTIC）在近40年后仍然是参考药物。最近FDA批准的药物显示出了希望，但患者的结果仍然有限，主要是由于耐药性。因此，组合靶向治疗受到越来越多的关注，并将随着新的分子靶点的发现而不断发展。改善黑色素瘤治疗的一个有吸引力的靶点是生长因子Nodal，其正常表达主要局限于胚胎发育，但在转移性黑色素瘤中被重新激活。在这项研究中，我们试图确定Nodal阳性的人类黑色素瘤细胞对DTIC治疗的反应，并确定靶向Nodal联合DTIC是否比单一治疗更有效。DTIC单次处理可抑制细胞生长，但不诱导细胞凋亡。DTIC不但没有降低Nodal的表达，反而增加了Nodal阳性亚群的大小，这一观察结果与细胞侵袭增加相一致。重要的是，来自难以接受DTIC治疗的黑色素瘤患者的临床组织标本在DTIC前和DTIC后的肿瘤中均呈Nodal表达阳性，强调了靶向Nodal的价值。在体外，抗nodal抗体单独对细胞增殖和凋亡有一定的不良影响，但DTIC联合抗nodal抗体联合治疗可协同抑制细胞生长，增加细胞凋亡，但浓度较单一治疗不能产生有意义的效果。靶向Nodal联合DTIC治疗有望治疗转移性黑色素瘤。
Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. Despite a complete response in fewer than 5% of patients, the chemotherapeutic agent Dacarbazine (DTIC) remains the reference drug after almost 40 years. More recently FDA approved drugs have shown promise but patient outcome remains modest, predominantly due to drug resistance. As such, combinatorial targeting has received increased attention, and will advance with the identification of new molecular targets. One attractive target for improving melanoma therapy is the growth factor Nodal, whose normal expression is largely restricted to embryonic development, but is reactivated in metastatic melanoma. In this study, we sought to determine how Nodal-positive human melanoma cells respond to DTIC treatment and to ascertain if targeting Nodal in combination with DTIC would be more effective than monotherapy. A single treatment with DTIC inhibited cell growth but did not induce apoptosis. Rather than reducing Nodal expression, DTIC increased the size of the Nodal-positive subpopulation, an observation coincident with increased cellular invasion. Importantly, clinical tissue specimens from patients with melanomas refractory to DTIC therapy stained positive for Nodal expression, both in pre- and post-DTIC tumors, underscoring the value of targeting Nodal. In vitro, anti-Nodal antibodies alone had some adverse effects on proliferation and apoptosis, but combining DTIC treatment with anti-Nodal antibodies decreased cell growth and increased apoptosis synergistically, at concentrations incapable of producing meaningful effects as monotherapy. Targeting Nodal in combination with DTIC therapy holds promise for the treatment of metastatic melanoma.