title: Honokiol radiosensitizes colorectal cancer cells: enhanced activity in cells with mismatch repair defects.
abstract: DNA mismatch repair is required for correcting any mismatches that are created during replication and recombination, and a defective mismatch repair system contributes to DNA damage-induced growth arrest. The colorectal cancer cell line HCT116 is known to have a mutation in the hMLH1 mismatch repair gene resulting in microsatellite instability and defective mismatch repair. Honokiol is a biphenolic compound that has been used in traditional Chinese medicine for treating various ailments including cancer. This study was designed to test the hypothesis that honokiol enhances the radiosensitivity of cancer cells with mismatch repair defect (HCT116) compared with those that are mismatch repair proficient (HCT116-CH3). We first determined that the combination of honokiol and γ-irradiation treatment resulted in dose-dependent inhibition of proliferation and colony formation in both cell lines. However, the effects were more pronounced in HCT116 cells. Similarly, the combination induced higher levels of apoptosis (caspase 3 activation, Bax to Bcl2 ratio) in the HCT116 cells compared with HCT116-CH3 cells. Cell cycle analyses revealed higher levels of dead cells in HCT116 cells. The combination treatment reduced expression of cyclin A1 and D1 and increased phosphorylated p53 in both cell lines, although there were significantly lower amounts of phosphorylated p53 in the HCT116-CH3 cells, suggesting that high levels of hMLH1 reduce radiosensitivity. These data demonstrate that honokiol is highly effective in radiosensitizing colorectal cancer cells, especially those with a mismatch repair defect.
authors.affiliation: Department of Medicine, Lanzhou University Second Hospital, Gansu Province, China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: He
authors.forename: Dharmalingam
authors.initials: D
authors.lastname: Subramaniam
authors.forename: Satish
authors.initials: S
authors.lastname: Ramalingam
authors.forename: Animesh
authors.initials: A
authors.lastname: Dhar
authors.forename: Russell G
authors.initials: RG
authors.lastname: Postier
authors.forename: Shahid
authors.initials: S
authors.lastname: Umar
authors.forename: Youcheng
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000235:genetics; D053843:DNA Mismatch Repair / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects* / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D017705:Lignans; D011838:Radiation-Sensitizing Agents; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols