Freund Eric, Liedtke Kim-Rouven, Miebach Lea, Wende Kristian, Heidecke Amanda, Kaushik Nagendra Kumar, Choi Eun Ha, Partecke Lars-Ivo, Bekeschus Sander
Department of General, Visceral, Thoracic and Vascular Surgery, Greifswald University Medical Centre, 17475 Greifswald, Germany.
Centre for Innovation competence (ZIK) plasmatis, Leibniz Institute for Plasma Science and Technology (INP Greifswald), 17489 Greifswald, Germany.
Cancers (Basel). 2020 Jan 2;12(1):122. doi: 10.3390/cancers12010122.
Colorectal carcinoma is among the most common types of cancers. With this disease, diffuse scattering in the abdominal area (peritoneal carcinosis) often occurs before diagnosis, making surgical removal of the entire malignant tissue impossible due to a large number of tumor nodules. Previous treatment options include radiation and its combination with intraperitoneal heat-induced chemotherapy (HIPEC). Both options have strong side effects and are often poor in therapeutic efficacy. Tumor cells often grow and proliferate dysregulated, with enzymes of the protein kinase family often playing a crucial role. The present study investigated whether a combination of protein kinase inhibitors and low-dose induction of oxidative stress (using hydrogen peroxide, HO) has an additive cytotoxic effect on murine, colorectal tumor cells (CT26). Protein kinase inhibitors from a library of 80 substances were used to investigate colorectal cancer cells for their activity, morphology, and immunogenicity (immunogenic cancer cell death, ICD) upon mono or combination. Toxic compounds identified in 2D cultures were confirmed in 3D cultures, and additive cytotoxicity was identified for the substances lavendustin A, GF109203X, and rapamycin. Toxicity was concomitant with cell cycle arrest, but except HMGB1, no increased expression of immunogenic markers was identified with the combination treatment. The results were validated for GF109203X and rapamycin but not lavendustin A in the 3D model of different colorectal (HT29, SW480) and pancreatic cancer cell lines (MiaPaca, Panc01). In conclusion, our in vitro data suggest that combining oxidative stress with chemotherapy would be conceivable to enhance antitumor efficacy in HIPEC.
结直肠癌是最常见的癌症类型之一。患有这种疾病时，在诊断前腹部区域常出现弥漫性播散（腹膜癌转移），由于大量肿瘤结节，使得手术切除全部恶性组织变得不可能。先前的治疗选择包括放疗及其与腹腔内热诱导化疗（HIPEC）的联合应用。这两种选择都有很强的副作用，且治疗效果往往不佳。肿瘤细胞常常生长和增殖失调，蛋白激酶家族的酶通常起着关键作用。本研究调查了蛋白激酶抑制剂与低剂量氧化应激诱导（使用过氧化氢，HO）联合应用是否对小鼠结直肠肿瘤细胞（CT26）具有相加的细胞毒性作用。使用来自80种物质库的蛋白激酶抑制剂来研究结肠癌细胞在单一应用或联合应用时的活性、形态和免疫原性（免疫原性癌细胞死亡，ICD）。在二维培养中鉴定出的有毒化合物在三维培养中得到证实，并且鉴定出薰衣草霉素A、GF109203X和雷帕霉素具有相加的细胞毒性。毒性与细胞周期停滞相伴，但联合治疗除了高迁移率族蛋白B1（HMGB1）外，未发现免疫原性标志物表达增加。在不同的结直肠癌（HT29、SW480）和胰腺癌细胞系（MiaPaca、Panc01）的三维模型中，对GF109203X和雷帕霉素的结果进行了验证，但对薰衣草霉素A未进行验证。总之，我们的体外数据表明，将氧化应激与化疗联合应用可能会提高HIPEC中的抗肿瘤疗效。
