3-吲哚甲胺31B和PS121912的抗肿瘤活性

Antitumor Activity of 3-Indolylmethanamines 31B and PS121912.

作者信息

Guthrie Margaret L, Sidhu Preetpal S, Hill Emily K, Horan Timothy C, Nandhikonda Premchendar, Teske Kelly A, Yuan Nina Y, Sidorko Marina, Rodali Revathi, Cook James M, Han Lanlan, Silvaggi Nicholas R, Bikle Daniel D, Moore Richard G, Singh Rakesh K, Arnold Leggy A

机构信息

Department of Chemistry and Biochemistry, University of Wisconsin, Milwaukee, WI, U.S.A. Milwaukee Institute of Drug Discovery, University of Wisconsin, Milwaukee, WI, U.S.A.

Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI, U.S.A.

出版信息

Anticancer Res. 2015 Nov;35(11):6001-7.

PMID:26504023

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4633305/

Abstract

AIM

To investigate the in vivo effects of 3-indolylmethanamines 31B and PS121912 in treating ovarian cancer and leukemia, respectively.

MATERIALS AND METHODS

Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and western blotting were applied to demonstrate the induction of apoptosis. Xenografted mice were investigated to show the antitumor effects of 3-indolylmethanamines. (13)C-Nuclear magnetic resource (NMR) and western blotting were used to demonstrate inhibition of glucose metabolism.

RESULTS

31B inhibited ovarian cancer cell proliferation and activated caspase-3, cleaved poly (ADP-ribose) polymerase 1 (PARP1), and phosphorylated mitogen-activated protein kinases (MAPK), JUN N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38. 31B reduced ovarian cancer xenograft tumor growth and PS121912 inhibited the growth of HL-60-derived xenografts without any sign of toxicity. Compound 31B inhibited de novo glycolysis and lipogenesis mediated by the reduction of fatty acid synthase and lactate dehydrogenase-A expression.

CONCLUSION

3-Indolylmethanamines represent a new class of antitumor agents. We have shown for the first time the in vivo anticancer effects of 3-indolylmethanamines 31B and PS121912.

摘要

目的

分别研究3 - 吲哚甲胺类化合物31B和PS121912在治疗卵巢癌和白血病中的体内作用。

材料与方法

采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法（TUNEL）和蛋白质免疫印迹法来证明细胞凋亡的诱导情况。通过对移植瘤小鼠的研究来显示3 - 吲哚甲胺类化合物的抗肿瘤作用。利用碳 - 13核磁共振波谱法（¹³C - NMR）和蛋白质免疫印迹法来证明对葡萄糖代谢的抑制作用。

结果

31B抑制卵巢癌细胞增殖，激活半胱天冬酶 - 3，切割聚（ADP - 核糖）聚合酶1（PARP1），并使丝裂原活化蛋白激酶（MAPK）、JUN氨基末端激酶/应激激活蛋白激酶（JNK/SAPK）和p38磷酸化。31B减少了卵巢癌移植瘤的生长，而PS121912抑制了HL - 60来源的移植瘤生长，且没有任何毒性迹象。化合物31B通过降低脂肪酸合酶和乳酸脱氢酶 - A的表达来抑制从头糖酵解和脂肪生成。