FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells

Abstract

Abstract. The inhibition of topoisomerase can suppress the growth of cancer cells and induce apoptosis. The aim of this study was to evaluate the anticancer effects and mechanisms of action of a novel topoisomerase inhibitor, 4-(furan-2-yl)-2-(pyridin-2-yl)-5,6-dihydro-1,10-phenanthroline (FPDHP). FPDHP suppressed the growth of Caki, A549, HT29 and MDA-MB-231 cells, and induced caspase-dependent apoptosis in the Caki cells. In particular, FPDHP also induced caspase-dependent apoptosis and the downregulation of the protein expression levels of cellular FLICE-like inhibitory protein (cFLIP) and the phosphorylation of Akt in Caki cells. Notably, the overexpression of cFLIP, but not that of Akt, in part, blocked the FPDHP-mediated apoptosis in Caki cells. In addition, FPDHP was further shown to induce the caspase-independent detachment of Caki cells from the culture dish; higher populations of apoptotic cells were observed in the detached cells than in the attached cells. To the best of our knoweledge, these results collectively demonstrate for the first time that FPDHP has a killing effect on Caki cells, which is mediated through both caspase-dependent apoptosis and caspase-independent cell detachment.

A novel anti‐cancer agent, FPDHP, induces anoikis in various human cancer cells through activation of calpain, and downregulation of anoikis‐related molecules

“…Next, we demonstrated the apoptotic mechanisms of FPDHP in various cancer cells. Like the previous report, 11 FPDHP induces caspase-dependent apoptosis in A549 and Caki cells ( Figure 4A-D). Mitochondria is a very important intracellular organelle, which play a crucial role in apoptosis by releasing AIF and cytochrome c, 16,17 subsequently, the activation of caspase-3 pathway is followed.…”

“…Previously we demonstrated that FPDHP induces cellular detachment in Caki human renal carcinoma cells. 11 Here, we reconfirmed cell detachment-inducing activity of FPDHP in other cancer cells. Using SRB assay, FPDHP induced cellular detachment of A549, HCT116, and Caki cells in dose (2-20 nM)-and time (1-3 h)-dependent manners, respectively ( Figure 1A-1G).…”

“…It has been reported that FPDHP downregulated the expression levels of p-Akt and c-FLIP proteins, however, the overexpression of cFLIP, but not that of p-Akt, led to a partial attenuation of FPDHP-induced apoptosis. 11 Interestingly, constitutive active form of Akt partially inhibited the cellular detachment induced by FPDHP ( Figure 3A), but constitutive active form of Akt did not suppressed FPDHP-induced apoptosis. 11 Although, more studies need to be performed on the regulatory mechanism of p-Akt in anoikis, it might be suggested that p-Akt plays an important role in cellular attachment than apoptosis.…”

“…Since the majority of anti‐cancer agents for controlling cancer have a mechanism of action to inhibit the growth of cancer cells, activate apoptotic pathway and induce the death of cancer cells, it is necessary to develop a potent anti‐cancer drug that can overcome the apoptotic resistance and suppress metastasis of cancer cells . FPDHP is a novel anti‐cancer candidate developed as a topoisomerase I selective inhibitor and has cytotoxic effects on cancer cell lines . However, the mechanisms of cancer cell detachment and apoptosis have not been yet fully investigated.…”

“…21 FPDHP is a novel anti-cancer candidate developed as a topoisomerase I selective inhibitor and has cytotoxic effects on cancer cell lines. 11 However, the mechanisms of cancer cell detachment and apoptosis have not been yet fully investigated. In the present study, we tried to evaluate the possibility of development as a new anticancer agent by analyzing the mechanisms of cellular detachment and apoptosis of FPDHP on various human cancer cells.…”