1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane potentiatesin vitroandin vivoantitumor effects of irinotecan on human colorectal cancer cells.
1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane (DPD), a diamantane derivative, was previously noted as an anticancer compound through anticancer drug screening with NCI-60 human tumor cells. Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is clinically active in the treatment of colorectal cancer, with no cross-resistance. The current study conducted a pharmacokinetic evaluation of DPD, an essential component of drug discovery. Subsequent pathway analysis of microarray gene expression data indicated that the anticancer mechanisms of DPD were associated with cell cycle progression and apoptosis. The combined effect of DPD and CPT-11 with regard to the mechanisms of apoptosis-related pathways in COLO 205 cells, and the antitumor effects in colon cancer xenograft mice, were investigated. The plasma concentration and pharmacokinetic parameters of DPD in male albino rats were analyzed following a single dose of DPD by injection. The protein expression of active caspase-3, procaspase-3 and poly ADP-ribose polymerase (PARP) in COLO 205 cells treated with DPD and CPT-11, alone or combined, was evaluated by western blotting. A trypan blue dye exclusion assay revealed that, whilst DPD alone demonstrated good antitumor effects, this effect was potentiated when combined with CPT-11. Combined treatment with DPD and CPT-11 upregulated the expression of cleaved PARP, procaspase-3, caspase-3 and active caspase-3 in COLO 205 cells. In the colon cancer xenograft model, compared with the control (vehicle-treated) mice, the sizes of the tumors were significantly lower in mice treated with DPD and CPT-11, alone or in combination. Thus, DPD may be a potential therapeutic agent for the treatment of colorectal cancer via upregulating apoptosis-related pathways.
Department of Surgery, Mackay Memorial Hospital, Taipei 10449, Taiwan R.O.C.; Department of Medicine, Mackay Medical College, New Taipei 25245, Taiwan R.O.C.
Po-Sheng
PS
Yang
Department of Nursing, National Taipei University of Nursing and Health Sciences, Taipei 11219, Taiwan R.O.C.
Jane-Jen
JJ
Wang
Department of Nursing, National Taipei University of Nursing and Health Sciences, Taipei 11219, Taiwan R.O.C.
Yea-Hwey
YH
Wang
Department of Nursing, Mackay Junior College of Medicine, Nursing and Management, Taipei 11260, Taiwan R.O.C.
Woan-Ching
WC
Jan
Department of Surgery, Mackay Memorial Hospital, Taipei 10449, Taiwan R.O.C.; Department of Medicine, Mackay Medical College, New Taipei 25245, Taiwan R.O.C.
Shih-Ping
SP
Cheng
Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan R.O.C.; Department of Horticulture and Biotechnology, Chinese Culture University, Taipei 11114, Taiwan R.O.C.
Yi-Chiung
YC
Hsu
1,6-bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane (DPD); COLO 205; NCI-60; apoptosis; colorectal cancer; irinotecan; microarray; pharmacokinetics