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Monomethyl Auristatin E Phosphate Inhibits Human Prostate Cancer Growth
Author(s) -
Cunningham David,
Parajuli Keshab R.,
Zhang Changde,
Wang Guangdi,
Mei Jiandong,
Zhang Qiuyang,
Liu Sen,
You Zongbing
Publication year - 2016
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.23226
Subject(s) - prostate cancer , medicine , in vivo , bone metastasis , cancer research , prostate , metastasis , flow cytometry , cell growth , cancer , viability assay , oncology , in vitro , pharmacology , chemistry , immunology , biochemistry , biology , microbiology and biotechnology
BACKGROUND Bone metastasis from primary prostate cancer leads to markedly diminished quality of life with poor long‐term survival. Bone seeking treatment options are limited with adverse consequences on rapidly proliferating tissues such as bone marrow. In the present study, we seek to determine the bone‐enriching capabilities of monomethyl auristatin E phosphate (MMAEp), a derivative of the potent antimitotic monomethyl auristatin E (MMAE). METHODS The in vitro actions and mechanisms of cytotoxicity were assessed using cell viability, immunofluorescence, flow cytometry, and Western blot analysis. In vivo efficacy was determined using an intratibial xenograft mouse model of human prostate cancer and live animal imaging. RESULTS The half maximal inhibitory concentration (IC50) of MMAE and MMAEp was determined to be approximately 2 and 48 nM, respectively, in PC‐3 and C4‐2B cell lines. MMAEp retained the mechanism of action of MMAE in reducing microtubule polymerization and stalling cell cycle progression at the G2/M transition. MMAEp was able to bind hydroxyapatite in in vitro assays. MMAEp significantly reduced intratibial tumor growth compared to the vehicle control treatment. CONCLUSIONS MMAEp is an antimitotic compound that binds to calcium ions in the bone and inhibits prostate tumor growth in the bone. Prostate 76:1420–1430, 2016 . © 2016 Wiley Periodicals, Inc.