Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells

被引：21

作者：

Gu, Mancang ^{[1
,2
,3
]}

Nishihara, Reiko ^{[1
,2
,4
,5
,6
,7
]}

Chen, Yang ^{[1
,2
,8
]}

Li, Wanwan ^{[1
,2
]}

Shi, Yan ^{[1
,2
,8
]}

Masugi, Yohei ^{[1
,2
]}

Hamada, Tsuyoshi ^{[1
,2
]}

Kosumi, Keisuke ^{[1
,2
]}

Liu, Li ^{[1
,2
,4
]}

da Silva, Annacarolina ^{[1
,2
]}

Nowak, Jonathan A. ^{[2
,7
]}

Twombly, Tyler ^{[1
,2
]}

Du, Chunxia ^{[1
,2
]}

Koh, Hideo ^{[1
,2
]}

Li, Wenbin ^{[1
,2
]}

Meyerhardt, Jeffrey A. ^{[2
,9
]}

Wolpin, Brian M. ^{[2
,9
]}

Giannakis, Marios ^{[2
,9
]}

Aguirre, Andrew J. ^{[2
,9
]}

Bass, Adam J. ^{[2
,9
,10
,11
]}

Drew, David A. ^{[2
,12
,13
]}

Chan, Andrew T. ^{[2
,12
,13
]}

Fuchs, Charles S. ^{[14
,15
,16
]}

Qian, Zhi Rong ^{[1
,2
,7
]}

Ogino, Shuji ^{[1
,2
,5
,7
]}

机构：

[1] Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02115 USA

[2] Harvard Med Sch, Boston, MA 02115 USA

[3] Zhejiang Chinese Med Univ, Coll Pharm, Hangzhou, Zhejiang, Peoples R China

[4] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA

[5] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[6] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA

[7] Brigham & Womens Hosp, Dept Pathol, Program MPE Mol Pathol Epidemiol, 75 Francis St, Boston, MA 02115 USA

[8] Chinese Peoples Liberat Army Gen Hosp, Med Oncol Dept 2, Beijing, Peoples R China

[9] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[10] Broad Inst MIT & Harvard, Cambridge, MA USA

[11] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA

[12] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA

[13] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA

[14] Yale Canc Ctr, New Haven, CT USA

[15] Yale Sch Med, Dept Med, New Haven, CT USA

[16] Smilow Canc Hosp, New Haven, CT USA

来源：

ONCOTARGET | 2017年 / 8卷 / 50期

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

anti-tumor effect; colorectal cancer; isogenic cell model; NSAID; PI3K; MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; TUMOR PIK3CA MUTATION; COLORECTAL-CANCER; CARDIOVASCULAR-DISEASE; PRIMARY PREVENTION; IN-VITRO; SURVIVAL; THERAPY; RISK; EXPRESSION;

D O I：

10.18632/oncotarget.20972

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Evidence suggests that nonsteroidal anti-inflammatory drug aspirin (acetylsalicylic acid) may improve patient survival in PIK3CA-mutant colorectal carcinoma, but not in PIK3CA-wild-type carcinoma. However, whether aspirin directly influences the viability of PIK3CA-mutant colon cancer cells is poorly understood. We conducted in vitro experiments to test our hypothesis that the anti-proliferative activity of aspirin might be stronger for PIK3CA-mutant colon cancer cells than for PIK3CA-wild-type colon cancer cells. We measured the anti-proliferative effect of aspirin at physiologic concentrations in seven PIK3CA-mutant and six PIK3CA-wildtype human colon cancer cell lines. After exposure to aspirin, the apoptotic index and cell cycle phase of colon cancer cells were assessed. In addition, the effect of aspirin was examined in parental SW48 cells and SW48 cell clones with individual knock-in PIK3CA mutations of either c. 3140A> G (p. H1047R) or c. 1633G> A (p. E545K). Aspirin induced greater dose-dependent loss of cell viability in PIK3CA-mutant cells than in PIK3CA-wild-type cells after treatment for 48 and 72 hours. Aspirin treatment also led to higher proportions of apoptotic cells and G0/G1 phase arrest in PIK3CA-mutant cells than in PIK3CA-wild-type cells. Aspirin treatment of isogenic SW48 cells carrying a PIK3CA mutation, either c. 3140A>G (p. H1047R) or c. 1633G>A (p. E545K), resulted in a more significant loss of cell viability compared to wild-type controls. Our findings indicate that aspirin causes cell cycle arrest, induces apoptosis, and leads to loss of cell viability more profoundly in PIK3CA-mutated colon cancer cells than in PIK3CA-wild- type colon cancer cells. These findings support the use of aspirin to treat patients with PIK3CA-mutant colon cancer.

引用

页码：87379 / 87389

页数：11