1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane potentiates in vitro and in vivo antitumor effects of irinotecan on human colorectal cancer cells

Abstract

Abstract. 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.

Potential therapeutic targets for growth arrest of colorectal cancer cells exposed to PTHrP

“…*P < 0.05, **P < 0.01. predict a favorable evolution in patients with CRC treated with CPT -11 (Charara et al, 2004). In addition, the activation of the apoptotic effector caspase-3 and consequently the cleavage of its substrate, poly-ADP ribose polymerase (PARP), are expected events once the CRC tumor cells respond to CPT-11 (Yang et al, 2016b). Taking into account that PTHrP exerts a protective effect under apoptotic conditions (Lezcano et al, 2013) and also negatively modulates several cell cycle inhibitors (Calvo et al, 2014), we decided to evaluate the expression of relevant molecular markers associated with these cellular responses in both Caco-2 cells and HCT116 cells treated with CPT-11 alone or in combination with PTHrP.…”