Sakharkar Meena Kishore, Dhillon Sarinder Kaur, Mazumder Mohit, Yang Jian
Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada.
Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
Genes Cancer. 2021 Mar 11;12:12-24. doi: 10.18632/genesandcancer.210. eCollection 2021.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal type of cancer. In this study, we undertook a pairwise comparison of gene expression pattern between tumor tissue and its matching adjacent normal tissue for 45 PDAC patients and identified 22 upregulated and 32 downregulated genes. PPI network revealed that fibronectin 1 and serpin peptidase inhibitor B5 were the most interconnected upregulated-nodes. Virtual screening identified bleomycin exhibited reasonably strong binding to both proteins. Effect of bleomycin on cell viability was examined against two PDAC cell lines, AsPC-1 and MIA PaCa-2. AsPC-1 did not respond to bleomycin, however, MIA PaCa-2 responded to bleomycin with an IC of 2.6 μM. This implicates that bleomycin could be repurposed for the treatment of PDAC, especially in combination with other chemotherapy agents. mouse xenograft studies and patient clinical trials are warranted to understand the functional mechanism of bleomycin towards PDAC and optimize its therapeutic efficacy. Furthermore, we will evaluate the antitumor activity of the other identified drugs in our future studies.
胰腺导管腺癌（PDAC）是一种致死率很高的癌症。在本研究中，我们对45例PDAC患者的肿瘤组织及其匹配的相邻正常组织之间的基因表达模式进行了成对比较，鉴定出22个上调基因和32个下调基因。蛋白质-蛋白质相互作用（PPI）网络显示，纤连蛋白1和丝氨酸蛋白酶抑制剂B5是上调基因中相互连接最多的节点。虚拟筛选发现博来霉素与这两种蛋白质均表现出相当强的结合力。针对两种PDAC细胞系AsPC-1和MIA PaCa-2检测了博来霉素对细胞活力的影响。AsPC-1对博来霉素无反应，然而，MIA PaCa-2对博来霉素有反应，其半数抑制浓度（IC）为2.6 μM。这意味着博来霉素可重新用于治疗PDAC，尤其是与其他化疗药物联合使用。有必要进行小鼠异种移植研究和患者临床试验，以了解博来霉素对PDAC的作用机制并优化其治疗效果。此外，我们将在未来的研究中评估其他已鉴定药物的抗肿瘤活性。
