McEwan David G, Brunton Valerie G, Baillie George S, Leslie Nicholas R, Houslay Miles D, Frame Margaret C
The Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Glasgow, United Kingdom.
Cancer Res. 2007 Jun 1;67(11):5248-57. doi: 10.1158/0008-5472.CAN-07-0097.
One of the major problems in treating colon cancer is chemoresistance to cytotoxic chemotherapeutic agents. There is therefore a need to devise new strategies to inhibit colon cancer cell growth and survival. Here, we show that a combination of low doses of the adenylyl cyclase activator forskolin together with the specific cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) inhibitor rolipram, but not the cAMP phosphodiesterase-3 (PDE3) inhibitor cilostamide, causes profound growth arrest of chemoresistant KM12C colon cancer cells. Low-dose forskolin causes KM12C cells to exit the cell cycle in G1 by inducing p27(Kip1) and primes cells for apoptosis on addition of rolipram. The effect of the low-dose forskolin/rolipram combination is mediated by displacement of the phosphatidylinositol 3,4,5-trisphosphate/phosphoinositide 3-kinase signaling module from the plasma membrane and suppression of the Akt/protein kinase-B oncogene pathway, to which KM12C cells are addicted for growth. The cAMP and phosphoinositide 3-kinase pathways form a critical intersection in this response, and reexpression of the tumor suppressor lipid phosphatase, phosphatase and tensin homologue, which is commonly lost or mutated in colon cancer, sensitizes KM12C cells to growth inhibition by challenge with low-dose forskolin. Certain chemoresistant colon cancer cells are therefore exquisitely sensitive to subtle elevation of cAMP by a synergistic low-dose adenylyl cyclase activator/PDE4 inhibitor combination. Indeed, these cells are addicted to maintenance of low cAMP concentrations in a compartment that is regulated by PDE4. Well-tolerated doses of PDE4 inhibitors that are already in clinical development for other therapeutic indications may provide an exciting new strategy for the treatment of colon cancer.
治疗结肠癌的主要问题之一是对细胞毒性化疗药物产生化学抗性。因此，需要设计新的策略来抑制结肠癌细胞的生长和存活。在此，我们表明，低剂量的腺苷酸环化酶激活剂福司可林与特异性环磷酸腺苷（cAMP）磷酸二酯酶-4（PDE4）抑制剂咯利普兰联合使用，但不是与cAMP磷酸二酯酶-3（PDE3）抑制剂西洛他唑联合使用，会导致化学抗性KM12C结肠癌细胞发生深度生长停滞。低剂量福司可林通过诱导p27（Kip1）使KM12C细胞在G1期退出细胞周期，并在添加咯利普兰时使细胞为凋亡做好准备。低剂量福司可林/咯利普兰组合的作用是通过将磷脂酰肌醇3,4,5-三磷酸/磷脂酰肌醇3-激酶信号模块从质膜上置换下来并抑制Akt/蛋白激酶B癌基因途径来介导的，KM12C细胞依赖该途径生长。cAMP和磷脂酰肌醇3-激酶途径在这种反应中形成关键交叉点，肿瘤抑制脂质磷酸酶、磷酸酶和张力蛋白同源物（在结肠癌中通常缺失或发生突变）的重新表达使KM12C细胞对低剂量福司可林刺激产生的生长抑制敏感。因此，某些化学抗性结肠癌细胞对低剂量腺苷酸环化酶激活剂/PDE4抑制剂组合协同引起的cAMP细微升高极为敏感。实际上，这些细胞依赖于由PDE4调节的隔室内低cAMP浓度的维持。已在临床上用于其他治疗适应症研发的耐受性良好的PDE4抑制剂剂量可能为结肠癌治疗提供令人兴奋的新策略。
