Abstract
Camptothecin-20(s)-O-(2-pyrazolyl-1)acetic ester (CPT6) is a novel semi-synthetic analog of camptothecin. In a previous report, CPT6 possessed higher cytotoxic activity in vitro towards human breast tumor MCF-7 cells than topotecan. In this study, the antitumor activity of CPT6 on the human breast tumor MCF-7 cell line was analyzed using the MTT method. The underlying mechanism of CPT6 action was investigated by analyzing the cell cycle distribution, apoptotic proportion, changes in mitochondrial membrane potential, and intracellular Ca2+ concentration using flow cytometry. Nuclear and mitochondrial morphologies were also observed by laser scanning confocal and transmission electron microscopy. DNA damage was observed in MCF-7 cells treated with CPT6. Low-dose CPT6 had a significant cytotoxic effect and could inhibit proliferation and induce apoptosis in MCF-7 cells, possibly through cell nucleus fragmentation and DNA damage. CPT6 thus appears to display potent antitumor activity against human breast tumor MCF-7 cells via the induction of apoptosis, and may be a useful alternative drug for breast cancer therapy.
Highlights
Camptothecin (CPT) is an alkaloid originally isolated from Camptotheca acuminate by Wall andWani in 1966 [1], and is one of the most important lead compounds in anticancer research
Fetal bovine serum (FBS), penicillin, streptomycin and trypsinase were purchased from Tianjin HaoYang Biological Manufacture Co., Ltd. (Tianjin, China). 3-(4,5Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), acridine orange (AO), dimethyl sulfoxide (DMSO), rhodamine 123 (Rh123) and propidium iodide (PI) were purchased from Sigma
We evaluated that the growth inhibitory activity of CPT6 was associated with the induction of DNA damage and apoptosis in MCF-7 cells
Summary
Camptothecin (CPT) is an alkaloid originally isolated from Camptotheca acuminate by Wall and. CPT derivatives (CPTs) have been shown to exhibit anticancer activity both in vitro and in vivo. 20-positions of CPT and obtained a series of CPT analogs, some pyridine quaternary salt derivatives of which showed good water solubility and potent antitumor activity both in vitro and in vivo [6,7]. The antitumor activity was related to the substituted positions, and to the substituent Among these derivatives, camptothecin-20(s)-O-(2-pyrazolyl-1)acetic ester (CPT6, Figure 1). Exhibited good antitumor activity in vitro, and demonstrated stronger cytotoxicity towards the human breast tumor MCF-7 cell line. The antiproliferative activity and the mechanism of action of CPT6 against human breast tumor MCF-7 cells, have not been reported. The antiproliferative activity of CPT6 against human breast tumor MCF-7 cells was analyzed using the MTT method. The mechanism of CPT6 action against human breast tumor MCF-7 cells was investigated by flow cytometry, laser scanning confocal microscopy (LSCM) and transmission electron microscopy (TEM)
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