Hwang Hae Hyun, Jeong Hee Jeong, Yun Sangwu, Byun Youngro, Okano Teruo, Kim Sung Wan, Lee Dong Yun
Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04763, Korea.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
Cancers (Basel). 2021 Nov 18;13(22):5775. doi: 10.3390/cancers13225775.
Pancreatic cancers are classified based on where they occur, and are grouped into those derived from exocrine and those derived from neuroendocrine tumors, thereby experiencing different anticancer effects under medication. Therefore, it is necessary to develop anticancer drugs that can inhibit both types. To this end, we developed a heparin-taurocholate conjugate, i.e., LHT, to suppress tumor growth via its antiangiogenic activity. Here, we conducted a study to determine the anticancer efficacy of LHT on pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET), in an orthotopic animal model. LHT reduced not only proliferation of cancer cells, but also attenuated the production of VEGF through ERK dephosphorylation. LHT effectively reduced the migration, invasion and tube formation of endothelial cells via dephosphorylation of VEGFR, ERK1/2, and FAK protein. Especially, these effects of LHT were much stronger on PNET (RINm cells) than PDAC (PANC1 and MIA PaCa-2 cells). Eventually, LHT reduced ~50% of the tumor weights and tumor volumes of all three cancer cells in the orthotopic model, via antiproliferation of cancer cells and antiangiogenesis of endothelial cells. Interestingly, LHT had a more dominant effect in the PNET-induced tumor model than in PDAC in vivo. Collectively, these findings demonstrated that LHT could be a potential antipancreatic cancer medication, regardless of pancreatic cancer types.
胰腺癌根据其发生部位进行分类，分为起源于外分泌腺的肿瘤和起源于神经内分泌的肿瘤，因此在药物治疗下会产生不同的抗癌效果。所以，有必要开发能够抑制这两种类型肿瘤的抗癌药物。为此，我们开发了一种肝素-牛磺胆酸盐共轭物，即LHT，通过其抗血管生成活性来抑制肿瘤生长。在此，我们在原位动物模型中进行了一项研究，以确定LHT对胰腺导管腺癌（PDAC）和胰腺神经内分泌肿瘤（PNET）的抗癌疗效。LHT不仅降低了癌细胞的增殖，还通过ERK去磷酸化减弱了VEGF的产生。LHT通过使VEGFR、ERK1/2和FAK蛋白去磷酸化，有效降低了内皮细胞的迁移、侵袭和管腔形成。特别是，LHT对PNET（RINm细胞）的这些作用比对PDAC（PANC1和MIA PaCa-2细胞）的作用要强得多。最终，在原位模型中，LHT通过抑制癌细胞增殖和内皮细胞抗血管生成，使所有三种癌细胞的肿瘤重量和肿瘤体积减少了约50%。有趣的是，在体内，LHT在PNET诱导的肿瘤模型中比在PDAC中具有更显著的效果。总的来说，这些发现表明，无论胰腺癌类型如何，LHT都可能是一种潜在的抗胰腺癌药物。
