Wang Kai, Huynh Nhi, Wang Xiao, Pajic Marina, Parkin Ashleigh, Man Jennifer, Baldwin Graham S, Nikfarjam Mehrdad, He Hong
Department of Surgery, University of Melbourne, Austin Health Studley Road, Heidelberg, Victoria 3084, Australia.
The Kinghorn Cancer Centre, The Garvan Institute of Medical Research 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
Am J Transl Res. 2019 Jun 15;11(6):3353-3364. eCollection 2019.
BACKGROUND/OBJECTIVE: Pancreatic ductal adenocarcinoma (PDA) remains the most lethal malignancy due to lack of an effective treatment. P21-activated kinases (PAKs) play a key role not only in cell proliferation and migration, but also in mediating chemo-resistance in PDA. The aim of this study was to investigate the combined effect of a PAK inhibitor PF-3758309 with multiple chemotherapeutic reagents on a panel of patient-derived PDA cell lines, and potential mechanisms involved.
Cells were treated with PF-3758309 plus or minus gemcitabine, 5-fluorouracil (5-FU) or abraxane, and cell growth was determined using a cell proliferation assay kit. Protein expression profiles were measured by Western blot. PDA cells were subcutaneously injected into the flanks of SCID mice which were then treated with saline, gemcitabine, PF-3758309, gemcitabine plus PF-3758309 or abraxane. Tumour growth was measured by volume and weight.
PAK1 was correlated with CK19 expression, and PAK4 with α-SMA and palladin expression. Combination of PF-3758309 with 5-FU, gemcitabine or abraxane further suppressed cell growth of patient-derived PDA cell lines . The combination of PF-3758309 with gemcitabine maximally inhibited tumour growth by suppressing cell proliferation. PF-3758309 inhibited the expression of HIF-1α, palladin and α-SMA both and .
PAK inhibitor PF-3758309 can enhance anti-tumour effects of multiple chemotherapeutic reagents on a panel of patient-derived PDA cell lines. Combination of PF-3758309 with gemcitabine achieves comparable efficacy to combination of gemcitabine with abraxane, and thus provides a potential targeted therapy in the management of PDA.
背景/目的：由于缺乏有效的治疗方法，胰腺导管腺癌（PDA）仍然是最致命的恶性肿瘤。p21激活激酶（PAKs）不仅在细胞增殖和迁移中起关键作用，而且在介导PDA的化疗耐药性中也起关键作用。本研究的目的是探讨PAK抑制剂PF-3758309与多种化疗药物联合应用对一组患者来源的PDA细胞系的联合作用及其潜在机制。
用PF-3758309加或不加吉西他滨、5-氟尿嘧啶（5-FU）或白蛋白结合型紫杉醇处理细胞，并用细胞增殖检测试剂盒测定细胞生长情况。通过蛋白质印迹法检测蛋白质表达谱。将PDA细胞皮下注射到SCID小鼠的侧腹，然后用生理盐水、吉西他滨、PF-3758309、吉西他滨加PF-3758309或白蛋白结合型紫杉醇处理。通过体积和重量测量肿瘤生长情况。
PAK1与CK19表达相关，PAK4与α-SMA和帕拉丁表达相关。PF-3758309与5-FU、吉西他滨或白蛋白结合型紫杉醇联合应用进一步抑制了患者来源的PDA细胞系的细胞生长。PF-3758309与吉西他滨联合应用通过抑制细胞增殖最大程度地抑制了肿瘤生长。PF-3758309在体内和体外均抑制HIF-1α、帕拉丁和α-SMA的表达。
PAK抑制剂PF-3758309可增强多种化疗药物对一组患者来源的PDA细胞系的抗肿瘤作用。PF-3758309与吉西他滨联合应用的疗效与吉西他滨与白蛋白结合型紫杉醇联合应用相当，因此为PDA的治疗提供了一种潜在的靶向治疗方法。
