ABSTRACT
Colon carcinoma represents a major problem in oncology, since this type of cancer responds poorly to conventional chemotherapy. Many groups are actively involved in the search of new experimental strategies to bypass this problem. We investigated the effects of 2-methoxyestradiol (2-ME), which derives from the NADPH-dependent cytochrome P450 metabolism of 17ß-estradiol. This compound has raised much interest in the past few decades for its inhibitory effects on the growth of cancer cells of different origin; however, little is known about its use on colon carcinoma-derived cell lines. In the present study, we investigated the effects of 2-ME on cell proliferation and cell cycle of two human colon carcinoma cell lines, namely HCT116 and SW613-B3. Our results showed a net anti-proliferative effect of 2-ME on both cell lines, which is accompanied by cell cycle arrest; moreover, we demonstrated that 2-ME is able to induce apoptosis as well as autophagy. This body of evidence points out that 2-ME could be considered as a promising tool against colon carcinoma.
Subject(s)
Colonic Neoplasms/drug therapy , Estradiol/analogs & derivatives , 2-Methoxyestradiol , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Autophagy/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Shape/drug effects , Cell Survival/drug effects , Colonic Neoplasms/pathology , DNA Fragmentation/drug effects , Estradiol/pharmacology , Estradiol/therapeutic use , Histones/metabolism , Humans , Mitochondria/drug effects , Mitochondria/metabolism , Phosphorylation/drug effects , Protein Processing, Post-Translational/drug effects , Tumor Stem Cell AssayABSTRACT
Drugs that are able to modulate the microtubule dynamics either by inhibiting tubulin polymerization or by blocking microtubule disassembly are of great interest in anti-cancer therapy; a number of them are currently applied in clinical development. Tubulin polymerization inhibitors, including arylthioindoles, are characterized by the presence of an indole nucleus and have been obtained from natural sources or prepared by semi-synthesis. We characterized the effect of 5-bromo-3-[(3,4,5-trimetoxyphenyl)thio]-1H-indole (RS 2518) on the metabolism of human cell lines derived from solid tumors. We found that this new compound impairs cell adhesion, arrests the cells in the G(2)/M cell cycle phase and inhibits cell proliferation, thus leading to apoptosis. The described effects of RS 2518 on cancer cells have led to its selection as a lead compound for further studies. Some analogues have been developed and tested on a panel of cancer cell lines.
