Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, Japan; Department of Phamacy, Municipal Ikeda Hospital, Japan.
Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, Japan.
Eur J Pharmacol. 2021 May 5;898:173957. doi: 10.1016/j.ejphar.2021.173957. Epub 2021 Mar 1.
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation in colon cancer contributes to the poor prognosis of the disease and chemoresistance of tumors. New therapies are needed; however, the lack of knowledge of the mechanism of chemoresistance has hindered progress. In this study, we investigated the mechanism of the reduced sensitivity of colon cancer cells to 5-fluorouracil (5-FU) and oxaliplatin (L-OHP), and the effects of perifosine, an Akt inhibitor that enhances the cytotoxicity of 5-FU and L-OHP in colon cancer cells harboring the PIK3CA mutation. The use of 5-FU or L-OHP alone or in combination induced significant death of Caco-2 cells (PIK3CA wild type), but only weakly decreased the viability of DLD-1 and SW948 cells harboring the PIK3CA mutation. The use of 5-FU and L-OHP, either alone or in combination, strongly suppressed Akt activation, Survivin, Bcl-2, and Bcl-xL expression, and enhanced Puma, phospho-p53, and p53 expression in Caco-2 cells than in DLD-1 cells. In addition, perifosine enhanced the cytotoxicity of the 5-FU and L-OHP combination, inhibited Akt activation and the expression of Survivin, Bcl-2, and Bcl-xL, and increased the expression of Puma, phospho-p53, and p53 in DLD-1 cells. These results indicate that PIK3CA mutation contributes to reduced sensitivity to 5-FU and L-OHP via Akt activation in colon cancer cells. Perifosine increases the efficacy of 5-FU and L-OHP by suppressing Akt activation. Thus, the use of an Akt inhibitor in combination with 5-FU and L-OHP may be beneficial in colon cancer with cells harboring the PIK3CA mutation.
磷酸肌醇-4,5-二磷酸 3-激酶催化亚单位α（PIK3CA）突变在结肠癌中导致疾病预后不良和肿瘤对化疗药物的耐药性。需要新的治疗方法；然而，对化疗耐药性机制的缺乏了解阻碍了进展。在这项研究中，我们研究了结肠癌细胞对 5-氟尿嘧啶（5-FU）和奥沙利铂（L-OHP）敏感性降低的机制，以及 Akt 抑制剂 perifosine 的作用，perifosine 增强了携带 PIK3CA 突变的结肠癌细胞中 5-FU 和 L-OHP 的细胞毒性。单独使用 5-FU 或 L-OHP 或联合使用均可显著诱导 Caco-2 细胞（PIK3CA 野生型）死亡，但仅弱降低携带 PIK3CA 突变的 DLD-1 和 SW948 细胞的活力。单独使用 5-FU 和 L-OHP，或联合使用，均可强烈抑制 Akt 激活、Survivin、Bcl-2 和 Bcl-xL 的表达，并增强 Caco-2 细胞中 Puma、磷酸化 p53 和 p53 的表达，而非 DLD-1 细胞。此外，perifosine 增强了 5-FU 和 L-OHP 联合使用的细胞毒性，抑制了 Akt 激活和 Survivin、Bcl-2 和 Bcl-xL 的表达，增加了 DLD-1 细胞中 Puma、磷酸化 p53 和 p53 的表达。这些结果表明，PIK3CA 突变通过激活 Akt 导致结肠癌细胞对 5-FU 和 L-OHP 的敏感性降低。Perifosine 通过抑制 Akt 激活来增加 5-FU 和 L-OHP 的疗效。因此，在携带 PIK3CA 突变的结肠癌中，使用 Akt 抑制剂与 5-FU 和 L-OHP 联合使用可能有益。
