Preclinical In Vitro, In Vivo, and Pharmacokinetic Evaluations of FLLL12 for the Prevention and Treatment of Head and Neck Cancers.
Despite its high promise for cancer prevention and therapy, the potential utility of curcumin in cancer is compromised by its low bioavailability and weak potency. The purpose of the current study was to assess the in vitro and in vivo efficacy and pharmacokinetic parameters of the potent curcumin analogue FLLL12 in SCCHN and identify the mechanisms of its antitumor effect. IC50 values against a panel of one premalignant and eight malignant head and neck cancer cell lines as well as apoptosis assay results suggested that FLLL12 is 10- to 24-fold more potent than natural curcumin depending on the cell line and induces mitochondria-mediated apoptosis. In vivo efficacy (xenograft) and pharmacokinetic studies also suggested that FLLL12 is significantly more potent and has more favorable pharmacokinetic properties than curcumin. FLLL12 strongly inhibited the expression of p-EGFR, EGFR, p-AKT, AKT, Bcl-2, and Bid and increased the expression of Bim. Overexpression of constitutively active AKT or Bcl-2 or ablation of Bim or Bid significantly inhibited FLLL12-induced apoptosis. Further mechanistic studies revealed that FLLL12 regulated EGFR and AKT at transcriptional levels, whereas Bcl-2 was regulated at the translational level. Finally, FLLL12 strongly inhibited the AKT downstream targets mTOR and FOXO1a and 3a. Taken together, our results strongly suggest that FLLL12 is a potent curcumin analogue with more favorable pharmacokinetic properties that induces apoptosis of head and neck cancer cell lines by inhibition of survival proteins including EGFR, AKT, and Bcl-2 and increasing of the proapoptotic protein Bim.
Department of Hematology and Medical Oncology and Winship Cancer Institute of Emory University, Atlanta, Georgia.
Abu Syed Md
AS
Anisuzzaman
Department of Hematology and Medical Oncology and Winship Cancer Institute of Emory University, Atlanta, Georgia.
Abedul
A
Haque
Department of Hematology and Medical Oncology and Winship Cancer Institute of Emory University, Atlanta, Georgia.
Mohammad Aminur
MA
Rahman
Department of Hematology and Medical Oncology and Winship Cancer Institute of Emory University, Atlanta, Georgia.
Dongsheng
D
Wang
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, Ohio.
James R
JR
Fuchs
Department of Pediatrics and Winship Cancer Institute of Emory University, Atlanta, Georgia.
Selwyn
S
Hurwitz
Biostatistics & Bioinformatics Shared Resource at Winship Cancer Institute, Department of Biostatistics & Bioinformatics, Rollins School of Public Health, Atlanta, Georgia.
Yuan
Y
Liu
Department of Pathology, Emory University School of Medicine, Atlanta, Georgia.
Gabriel
G
Sica
Department of Hematology and Medical Oncology and Winship Cancer Institute of Emory University, Atlanta, Georgia.
Fadlo R
FR
Khuri
Department of Hematology and Medical Oncology and Winship Cancer Institute of Emory University, Atlanta, Georgia.
Zhuo Georgia
ZG
Chen
Department of Hematology and Medical Oncology and Winship Cancer Institute of Emory University, Atlanta, Georgia.
Dong M
DM
Shin
Department of Hematology and Medical Oncology and Winship Cancer Institute of Emory University, Atlanta, Georgia. aamin9@emory.edu.
A R M Ruhul
AR
Amin
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D017209:Apoptosis; D001682:Biological Availability; D045744:Cell Line, Tumor; D003474:Curcumin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000517:prevention & control*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results
D000970:Antineoplastic Agents; C541487:FLLL-12 compound; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D066246:ErbB Receptors; D003474:Curcumin