Bar-Yehuda Sara, Madi Lea, Silberman Daniel, Gery Slosman, Shkapenuk Maya, Fishman Pnina
Can-Fite BioPharma Ltd., Kiryat-Matalon, Petach-Tikva 49170, Israel.
Neoplasia. 2005 Jan;7(1):85-90. doi: 10.1593/neo.04364.
NF-kappaB and the upstream kinase PKB/Akt are highly expressed in chemoresistance tumor cells and may hamper the apoptotic pathway. CF101, a specific agonist to the A3 adenosine receptor (A3AR), inhibits the development of colon carcinoma growth in cell cultures and xenograft murine models. Because CF101 has been shown to downregulate PKB/Akt and NF-kappaB protein expression level, we presumed that its combination with chemotherapy will enhance the antitumor effect of the cytotoxic drug. In this study, we utilized 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays and a colon carcinoma xenograft model. It has been shown that a combined treatment of CF101 and 5-fluorouracil (5-FU) enhanced the cytotoxic effect of the latter on HCT-116 human colon carcinoma cell proliferation and tumor growth. Downregulation of PKB/Akt, NF-kappaB, and cyclin D1, and upregulation of caspase-3 protein expression level were observed in cells and tumor lesions on treatment with a combination of CF101 and 5-FU. Moreover, in mice treated with the combined therapy, myelotoxicity was prevented as was evidenced by normal white blood cell and neutrophil counts. These results show that CF101 potentiates the cytotoxic effect of 5-FU, thus preventing drug resistance. The myeloprotective effect of CF101 suggests its development as an add-on treatment to 5-FU.
核因子-κB（NF-κB）和上游激酶蛋白激酶B/蛋白激酶B（PKB/Akt）在化疗耐药肿瘤细胞中高表达，可能会阻碍凋亡途径。CF101是A3腺苷受体（A3AR）的特异性激动剂，在细胞培养和异种移植小鼠模型中可抑制结肠癌生长。由于CF101已被证明可下调PKB/Akt和NF-κB蛋白表达水平，我们推测其与化疗联合使用将增强细胞毒性药物的抗肿瘤作用。在本研究中，我们使用了3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴盐（MTT）和集落形成试验以及结肠癌异种移植模型。结果表明，CF101与5-氟尿嘧啶（5-FU）联合治疗增强了后者对HCT-116人结肠癌细胞增殖和肿瘤生长的细胞毒性作用。在用CF101和5-FU联合治疗的细胞和肿瘤病变中，观察到PKB/Akt、NF-κB和细胞周期蛋白D1的下调以及半胱天冬酶-3蛋白表达水平的上调。此外，在接受联合治疗的小鼠中，骨髓毒性得到预防，白细胞和中性粒细胞计数正常证明了这一点。这些结果表明，CF101增强了5-FU的细胞毒性作用，从而防止了耐药性。CF101的骨髓保护作用表明其可作为5-FU的附加治疗药物进行开发。
