Functional Biological Activity of Sorafenib as a Tumor-Treating Field Sensitizer for Glioblastoma Therapy.
Functional Biological Activity of Sorafenib as a Tumor-Treating Field Sensitizer for Glioblastoma Therapy.
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DOI：
10.3390/ijms19113684
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发表时间：
2018-11-21
影响因子：
5.6
通讯作者：
Yoon M
中科院分区：
文献类型：
--
作者：
Jo Y;Kim EH;Sai S;Kim JS;Cho JM;Kim H;Baek JH;Kim JY;Hwang SG;Yoon M
胶质母细胞瘤是成人最常见的原发性脑肿瘤，是一种无法治愈的恶性肿瘤，短期生存率低，通常采用放疗沿着替莫唑胺治疗。虽然肿瘤治疗场（TTFields）的开发，即低强度和中等强度交替电场促进了胶质母细胞瘤的治疗，但据报告TTFields的临床结局不一致。然而，已证明化疗与TTFields联合给药对胶质母细胞瘤患者有效。索拉非尼是一种抗增殖和促凋亡剂，被用作胶质母细胞瘤的一线治疗。本研究旨在研究索拉非尼在体外和体内对TTFields诱导的胶质母细胞瘤细胞抗肿瘤和抗血管生成反应的影响。索拉非尼使胶质母细胞瘤细胞对TTFields敏感，如TTFields后细胞活力显著降低（p < 0.05）所示，索拉非尼和TTFields联合治疗通过活性氧（ROS）生成加速细胞凋亡，如聚（ADP-核糖）聚合酶（PARP）裂解所示。此外，使用索拉非尼+TTFields增加了自噬，从LC 3上调和自噬空泡形成中可以看出。细胞周期标志物积累，细胞经历G2/M期阻滞，G 0/G1期细胞比率增加。此外，联合治疗显著抑制肿瘤细胞的运动性和侵袭性，以及血管生成。我们的结果表明，索拉非尼和TTFields联合治疗略优于单独治疗，可能用于临床治疗胶质母细胞瘤，这需要进一步研究。
Glioblastoma, the most common primary brain tumor in adults, is an incurable malignancy with poor short-term survival and is typically treated with radiotherapy along with temozolomide. While the development of tumor-treating fields (TTFields), electric fields with alternating low and intermediate intensity has facilitated glioblastoma treatment, clinical outcomes of TTFields are reportedly inconsistent. However, combinatorial administration of chemotherapy with TTFields has proven effective for glioblastoma patients. Sorafenib, an anti-proliferative and apoptogenic agent, is used as first-line treatment for glioblastoma. This study aimed to investigate the effect of sorafenib on TTFields-induced anti-tumor and anti-angiogenesis responses in glioblastoma cells in vitro and in vivo. Sorafenib sensitized glioblastoma cells to TTFields, as evident from significantly decreased post-TTFields cell viability (p < 0.05), and combinatorial treatment with sorafenib and TTFields accelerated apoptosis via reactive oxygen species (ROS) generation, as evident from Poly (ADP-ribose) polymerase (PARP) cleavage. Furthermore, use of sorafenib plus TTFields increased autophagy, as evident from LC3 upregulation and autophagic vacuole formation. Cell cycle markers accumulated, and cells underwent a G2/M arrest, with an increased G0/G1 cell ratio. In addition, the combinatorial treatment significantly inhibited tumor cell motility and invasiveness, and angiogenesis. Our results suggest that combination therapy with sorafenib and TTFields is slightly better than each individual therapy and could potentially be used to treat glioblastoma in clinic, which requires further studies.
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影响因子：
3.5
作者：
Constantinescu CC;Mukherjee J
通讯作者：
Mukherjee J
影响因子：
9
作者：
Karanam NK;Srinivasan K;Ding L;Sishc B;Saha D;Story MD
通讯作者：
Story MD
影响因子：
11.2
作者：
Plastaras, John P.;Kim, Seok-Hyun;El-Deiry, Wafik S.
通讯作者：
El-Deiry, Wafik S.
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
2
作者：
Clark, Paul A.;Gaal, Jordan T.;Robins, H. Ian
通讯作者：
Robins, H. Ian