David Cunningham1, Keshab R Parajuli1, Changde Zhang2, Guangdi Wang2, Jiandong Mei1,3, Qiuyang Zhang1, Sen Liu1, Zongbing You4,5,6,7,8. 1. Department of Structural and Cellular Biology, Tulane University, New Orleans, Louisiana. 2. Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, Louisiana. 3. Department of Thoracic Surgery, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China. 4. Department of Structural and Cellular Biology, Tulane University, New Orleans, Louisiana. zyou@tulane.edu. 5. Department of Orthopaedic Surgery, Tulane University, New Orleans, Louisiana. zyou@tulane.edu. 6. Tulane Cancer Center, Louisiana Cancer Research Consortium, Tulane University, New Orleans, Louisiana. zyou@tulane.edu. 7. Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University, New Orleans, Louisiana. zyou@tulane.edu. 8. Tulane Center for Aging, Tulane University, New Orleans, Louisiana. zyou@tulane.edu.
Abstract
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.
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.
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