Phospho-Aspirin (MDC-22) inhibits pancreatic cancer growth in patient-derived tumor xenografts and KPC mice by targeting EGFR: Enhanced efficacy in combination with irinotecan

被引:7
作者
Lanzi, Cecilia Rodriguez [1 ]
Wei, Ran [2 ,6 ]
Luo, Dingyuan [1 ,3 ,4 ]
Mackenzie, Gerardo G. [1 ,5 ,6 ]
机构
[1] Univ Calif Davis, Dept Nutr, One Shields Ave, Davis, CA 95616 USA
[2] Zhejiang Agr & Forestry Univ, Dept Tea Sci, Hangzhou 311300, Peoples R China
[3] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Med Res Ctr, Dept Thyroid Surg, Guangzhou 510120, Peoples R China
[4] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Med Res Ctr, Guangdong Prov Key Lab Malignant Tumor Epigenet &, Guangzhou 510120, Peoples R China
[5] SUNY Stony Brook, Dept Family Populat & Prevent Med, Stony Brook, NY 11794 USA
[6] Univ Calif Davis, Comprehens Canc Ctr, Sacramento, CA 95817 USA
来源
NEOPLASIA | 2022年 / 24卷 / 02期
关键词
Pancreatic cancer; KPC; Phospho-Aspirin; EGFR; irinotecan; FAK; MDC-22; FOCAL ADHESION KINASE; COLON-CANCER; ANTIINFLAMMATORY DRUGS; SULINDAC OXT-328; FACTOR RECEPTOR; CELL INVASION; CARCINOGENESIS; GEMCITABINE; PATHWAYS; KRAS;
D O I
10.1016/j.neo.2021.12.004
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Novel therapeutic strategies are needed in the fight against pancreatic cancer. We have previously documented the chemopreventive effect of MDC-22 in preclinical models of pancreatic cancer. In the present work, we examined the therapeutic effects of MDC-22 in patient-derived tumor xenografts (PDTXs) and in LSL-Kras(G12D/+), LSL-Trp53(R172H/+), Pdx1-Cre (KPC) genetically engineered mice, two complementary and clinically relevant animal models of pancreatic cancer. In addition, we evaluated whether MDC-22 could synergize with current chemotherapeutic drugs used in the clinic. MDC-22 reduced the growth of various human pancreatic cancer cell lines in a concentration-dependent manner. In vivo, MDC-22 strongly reduced patient-derived pancreatic tumor xenograft growth by 50%, and extended survival of LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx1-Cre (KPC) mice by over a month (5.3 months versus 7.0 months). In both models, MDC-22 inhibited EGFR activation and its downstream signals, including ERK and FAK phosphorylation. In human pancreatic cancer cell lines, MDC-22 enhanced the growth inhibitory effect of irinotecan, and to a lesser degree those of gemcitabine and nab-paclitaxel. Normal human pancreatic epithelial cells were more resistant to the cytotoxic effects of, both, MDC-22 alone or in combination with irinotecan, indicating selectivity. Furthermore, MDC-22 enhanced irinotecan's effect on cell migration, in part, by inhibiting EGFR/FAK signaling. Collectively, our results indicate that MDC-22 is an effective anticancer drug in preclinical models of pancreatic cancer, and suggest that MDC-22 plus irinotecan as drug combination strategy for pancreatic cancer treatment, which warrants further evaluation.
引用
收藏
页码:133 / 144
页数:12
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