Tumor vessel normalization by the PI3K inhibitor HS-173 enhances drug delivery. (10th September 2017)

• Record Type: Journal Article
• Authors: Kim, Soo Jung; Jung, Kyung Hee; Son, Mi Kwon; Park, Jung Hee; Yan, Hong Hua; Fang, Zhenghuan; Kang, Yeo Wool; Han, Boreum; Lim, Joo Han; Hong, Soon-Sun
• Is Part Of: Cancer letters. Volume 403(2017)
• Page Start: 339
• Page End: 353
• Publication Date: 2017-09-10
• Subjects: PI3K inhibitor -- Cancer drug delivery -- Tumor vessel normalization; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.06.035
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Tumor vessels are leaky and immature, which causes poor oxygen and nutrient supply to tumor vessels and results in cancer cell metastasis to distant organs. This instability of tumor blood vessels also makes it difficult for anticancer drugs to penetrate and reach tumors. Numerous tumor vessel normalization approaches have been investigated for improving drug delivery into tumors. In this study, we investigated whether phosphoinositide 3-kinase (PI3K) inhibitors are able to improve vascular structure and function over the prolonged period necessary to achieve effective vessel normalization. The PI3K inhibitors, HS-173 and BEZ235 potently suppressed tumor growth and hypoxia, and increased tumor apoptosis in animal models. PI3K inhibitors also induced a regular, flat monolayer of endothelial cells (ECs) in vessels, improving stability of vessel structure, and normalized tumor vessels by increasing vascular maturity, pericyte coverage, basement membrane thickness, and tight-junctions. These effects resulted in a decrease in tumor vessel tortuosity and vessel thinning, and improved vessel function and blood flow. The tumor vessel stabilization effect of the PI3K inhibitor HS-173 also decreased the number of metastatic lung nodules in vivo metastasis model. Furthermore, HS-173 improved the delivery of doxorubicin into the tumor region, enhancing its anticancer effects. Mechanistic studies suggested that PI3K inhibitor HS-173-induced vessel normalization reflected changes in endothelial Notch signaling. Taken together, our findings indicate that vessel normalization by PI3K inhibitors restrained tumor growth and metastasis while improving chemotherapy by enhancing drug delivery into the tumor, suggesting that HS-173 may have a therapeutic value as an enhancer or an anticancer drug. Highlights: Tumor vessels are leaky and immature, which causes poor oxygen and nutrient supply, resulting in cancer cell metastasis. HS-173 caused vessel normalization in tumors, inhibiting vascular leakage and neoangiogenesis. In combination therapy, HS-173 increased blood perfusion and led to delayed tumor growth. Vessel normalization by HS-173 could be a novel therapeutic strategy for inhibiting tumor growth by improving drug delivery.