Silibinin suppresses growth and induces apoptotic death of human colorectal carcinoma LoVo cells in culture and tumor xenograft.
Colorectal cancer is one of the leading causes of cancer-related morbidity and mortality. The use of nontoxic phytochemicals in the prevention and intervention of colorectal cancer has been suggested as an alternative to chemotherapy. Here we assessed the anticancer efficacy of silibinin against advanced colorectal cancer LoVo cells both in vitro and in vivo. Our results showed that silibinin treatment strongly inhibits the growth of LoVo cells (P < 0.05-0.001) and induces apoptotic death (P < 0.01-0.001), which was associated with increased levels of cleaved caspases (3 and 9) and cleaved poly(ADP-ribose) polymerase. Additionally, silibinin caused a strong cell cycle arrest at G(1) phase and a slight but significant G(2)-M-phase arrest at highest concentration (P < 0.01-0.001). Molecular analyses for cell cycle regulators showed that silibinin decreases the level of cyclins (D1, D3, A and B1) and cyclin-dependent kinases (1, 2, 4, and 6) and increases the level of cyclin-dependent kinase inhibitors (p21 and p27). Consistent with these results, silibinin treatment also decreased the phosphorylation of retinoblastoma protein at Ser(780), Ser(795), and Ser(807)/Ser(811) sites without significantly affecting its total level. In animal studies, oral administration of silibinin for 6 weeks (at 100 and 200 mg/kg/d for 5 days/wk) significantly inhibited the growth of LoVo xenograft (P < 0.001) in athymic nude mice without any apparent toxicity. Analyses of xenograft tissue showed that silibinin treatment inhibits proliferation and increases apoptosis along with a strong increase in p27 levels but a decrease in retinoblastoma phosphorylation. Together, these results suggest the potential use of silibinin against advanced human colorectal cancer.
Kaur
Manjinder
M
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado-Denver, Aurora, Colorado 80045, USA.
Velmurugan
Balaiya
B
Tyagi
Alpna
A
Deep
Gagan
G
Katiyar
Suchitra
S
Agarwal
Chapla
C
Agarwal
Rajesh
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016923:Cell Death; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000077385:Silybin; D012838:Silymarin / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D012838:Silymarin; D000077385:Silybin