Antitumor Activity of 3-Indolylmethanamines 31B and PS121912

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

Antitumor Activity of 3-Indolylmethanamines 31B and PS121912

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

Authors

Margaret L Guthrie¹, Preetpal S Sidhu¹, Emily K Hill², Timothy C Horan², Premchendar Nandhikonda¹, Kelly A Teske¹, Nina Y Yuan¹, Marina Sidorko¹, Revathi Rodali¹, James M Cook¹, Lanlan Han¹, Nicholas R Silvaggi¹, Daniel D Bikle³, Richard G Moore², Rakesh K Singh², Leggy A Arnold⁴

Affiliations

¹ 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.
² 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.
³ Endocrine Research Unit, Department of Medicine, Veterans Affairs Medical Center, San Francisco, CA, U.S.A.
⁴ 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. arnold2@uwm.edu.

PMID: 26504023
PMCID: 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.

Keywords: 3-Indolylmethanamine; leukemia; ovarian cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amines / chemistry*
Aniline Compounds / pharmacology*
Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Blotting, Western
Cell Proliferation / drug effects
Female
Flow Cytometry
Humans
Hydrocarbons, Aromatic / pharmacology*
Indoles / chemistry*
Indoles / pharmacology
Magnetic Resonance Spectroscopy
Mice
Mice, Nude
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

4-chloro-N-((2-chlorophenyl)(2-methyl-1H-indol-3-yl)methyl)aniline
Amines
Aniline Compounds
Antineoplastic Agents
Hydrocarbons, Aromatic
Indoles
PS121912

Abstract

Publication types

MeSH terms

Substances

Grants and funding