Immunohistochemical assessment of possible anticancer effect mechanisms of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)- 5,6,7-trichloro-1,3-tropolone in PDX models of lung cancer

E. F. Komarova, E. Lukbanova, E. Dzhenkova, A. Goncharova, E. Zaikina, S. Gurova, A. V. Galina, L. K. Kurbanova, M. V. Mindar, D. Khodakova, M. S. Gusareva, M. Zinkovich
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Abstract

Purpose of the study. Evaluation of the expression of immunohistochemical tumor markers Ki-67, b-catenin, Bcl-2, P53, connexin 32 and connexin 43 when using 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone in mice with xenographs of squamous cell lung cancer.Materials and methods. Subcutaneous PDX models of human squamous cell lung cancer were created in immunodeficient BALB/c Nude mice. A fragment of the patient’s tumor (3 × 3 × 3 mm) was implanted subcutaneously in the right thigh of a previously anesthetized mouse. 200 μl of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone was administered orally using a probe in 12 doses once every 3 days. All animals were divided into groups depending on the tropolone doses: experimental groups 2–5 with doses of 0.0055, 0.055, 0.55 and 2.75 mg/g, respectively. The control group received 1 % starch gel which was tropolone carrier. The animals were euthanized 36 days after the start of the substance administration, and the tumor tissue was isolated and prepared for the IHC study according to the standard protocol. IHC reactions were performed using antibodies for Ki-67, b-catenin, Bcl-2, P53, connexin 32 and connexin 43.Results. Higher tropolone doses were associated with decreased expression of Ki-67, b-catenin, and the Bcl-2 protein, but increased expression of the P53 protein. The dosage of tropolone and expression of connexin 43 were directly proportional.Conclusion. Immunohistochemical analysis of expression of proteins in PDX models of human squamous cell lung cancer when using 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone showed the changes indicating its antitumor efficacy and suggesting a possible mechanism of action based on the activation of apoptosis.
2-(6,8-二甲基-5-硝基-4-氯喹啉-2-基)- 5,6,7-三氯-1,3-tropolone对肺癌PDX模型可能的抗癌作用机制的免疫组化评价
研究目的:2-(6,8-二甲基-5-硝基-4-氯喹啉-2-基)-5,6,7-三氯-1,3-tropolone对鳞状细胞肺癌小鼠免疫组化肿瘤标志物Ki-67、b-catenin、Bcl-2、P53、连接蛋白32、连接蛋白43表达的影响材料和方法。在免疫缺陷BALB/c裸鼠中建立人鳞状细胞肺癌皮下PDX模型。将患者肿瘤碎片(3 × 3 × 3 mm)皮下植入先前麻醉的小鼠右大腿。用探针口服2-(6,8-二甲基-5-硝基-4-氯喹啉-2-基)-5,6,7-三氯-1,3-tropolone 200 μl,共12次,每3 d 1次。所有动物根据tropolone剂量分为实验组2-5组,剂量分别为0.0055、0.055、0.55和2.75 mg/g。对照组给予1%淀粉凝胶作为tropolone载体。在给药36天后对动物实施安乐死,并根据标准方案分离肿瘤组织,准备进行免疫组化研究。采用Ki-67、b-连环蛋白、Bcl-2、P53、连接蛋白32和连接蛋白43抗体进行免疫组化反应。高剂量的tropolone与Ki-67、b-catenin和Bcl-2蛋白表达降低相关,但与P53蛋白表达升高相关。tropolone的用量与connexin 43的表达成正比。免疫组化分析2-(6,8-二甲基-5-硝基-4-氯喹啉-2-基)-5,6,7-三氯-1,3-tropolone对人鳞状细胞肺癌PDX模型中蛋白表达的影响表明其抗肿瘤作用的变化,并提示其可能基于激活细胞凋亡的作用机制。
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