PI3K/mTOR 抑制劑強化cisplatin及etoposide於小細胞肺癌的抗癌效果之研究

Abstract

小細胞肺癌是肺癌種類中最具侵略性的，約占所有肺癌的15%，有著快速生長、早期轉移和產生抗藥性的特點，因其可使用的治療策略有限，小細胞肺癌患者的臨床治療預期表現不佳，極需要新的治療策略。傳統上cisplatin及etoposide的合併治療是小細胞肺癌的第一線用藥，而BEZ235是一新型的標靶藥物，已經廣泛的試驗於多種癌症，目前於臨床試驗的第一、二階段。本研究著重於測試PI3K/mTOR抑制劑:BEZ235是否能加強cisplatin或etoposide於小細胞肺癌的抗腫瘤效果、觀察在訊息傳遞路徑上的表現以及異體移植人類小細胞肺癌的免疫缺陷裸鼠動物模式。研究結果證實在H146及H209小細胞肺癌株中，BEZ235合併cisplatin及etoposide皆表現明顯的細胞毒殺效果以及誘發細胞凋亡，且能有效減少cisplatin及etoposide的用量，在PI3K/AKT/mTOR訊息傳遞路徑中BEZ235合併cisplatin及etoposide加強影響抑制AKT、S6的磷酸化表現，動物模式中合併藥物使用也能更有效抑制腫瘤生長。總結而言，BEZ235和cisplatin或etoposide合併治療能有效抑制小細胞肺癌生長，增加細胞凋亡，且提供了降低cisplatin、etoposide藥物使用量的可能，並有機會減少藥物使用的副作用，因此此合併治療在小細胞肺癌上或許可作為一種新的標靶治療策略。

Background: Small cell lung cancer (SCLC) is an aggressive malignance disease with distant metastasis and faster growth rates. First line therapy in SCLC consists of cisplatin combining with etoposide, but the SCLC relapse rates are high, prognosis remains poor and has severe side effects. The SCLC treatments lack of breakthrough and standard treatment regimen unchanged over 3 decades. Thence, the new combination treatments are needed in order to improve the prognosis of SCLC. BEZ235, a novel dual PI3K/mTOR inhibitor, is used in phase I/II clinical trials for colorectal, breast, renal, prostate cancer and acute leukemia. It is not used in SCLC clinical trials, but studies have reported that BEZ235 has potent antitumor activity in SCLC. Therefore, we try to combine cisplatin or etoposide with BEZ235 as adjuvant treatment for SCLC.

Methods: We first investigate the combination of BEZ235 with cisplatin or etoposide treating on H146 and H209 SCLC cell lines. The anticancer effects of various combinations are determined in terms of cell viability, apoptosis, and BEZ235-regulated proteins. We also evaluate the efficacy of BEZ235/cisplatin, BEZ235/etoposide combination in H209 xenograft nude mice.

Result: Our data show that both BEZ235/cisplatin and BEZ235/etoposide lower the concentration of cisplatin or etoposide to inhibit cell growth and induce more apoptosis in SCLC cells. We also find the combined treatment inducing BEZ235 regulated protein expressions, which leads to increase antitumor effects in SCLC cell lines. Furthermore, the combination treatments enhance shrinking tumor volumes.

Conclusions: This study confirms that BEZ235 combined treatments promote the cytotoxicity and lower the dosage of cisplatin and etoposide. We suggest that BEZ235 combined with cisplatin or etoposide is a promising and effective regimen.