Antitumor Activity of Americanin A Isolated from the Seeds of Phytolacca americana by Regulating the ATM/ATR Signaling Pathway and the Skp2–p27 Axis in Human Colon Cancer Cells

Abstract

The antiproliferative and antitumor activities of americanin A (1), a neolignan isolated from the seeds of Phytolacca americana, were investigated in human colon cancer cells. Compound 1 inhibited the proliferation of HCT116 human colon cancer cells both in vitro and in vivo. The induction of G2/M cell-cycle arrest by 1 was concomitant with regulation of the ataxia telangiectasia-mutated/ATM and Rad3-related (ATM/ATR) signaling pathway. Treatment with 1 activated ATM and ATR, initiating the subsequent signal transduction cascades that include checkpoint kinase 1 (Chk1), checkpoint kinase 2 (Chk2), and tumor suppressor p53. Another line of evidence underlined the significance of 1 in regulation of the S phase kinase-associated protein 2 (Skp2)-p27 axis. Compound 1 targeted selectively Skp2 for degradation and thereby stabilized p27. Therefore, compound 1 suppressed the activity of cyclin B1 and its partner cell division cycle 2 (cdc2) to prevent entry into mitosis. Furthermore, prolonged treatment with 1 induced apoptosis by producing excessive reactive oxygen species. The intraperitoneal administration of 1 inhibited the growth of HCT116 tumor xenografts in nude mice without any overt toxicity. Modulation of the ATM/ATR signaling pathway and the Skp2-p27 axis might be plausible mechanisms of action for the antiproliferative and antitumor activities of 1 in human colon cancer cells.

Prp19 Arrests Cell Cycle via Cdc5L in Hepatocellular Carcinoma Cells

“…Furthermore Prp19 bound with Cdc5L and participated in mitotic processing by modulating Cdc5L. Recently, therapeutic modalities such as anti-mitotic drugs are booming [4], and some pharmaceutical products exert antitumor effects by inducing cell cycle arrest at the G2/M phase [24,25,26],suggesting that the inhibition of Prp19C could be a targeted anti-mitotic cancer therapy. This may provide theoretical basis to elucidate the role of Prp19C during the pathogenesis of HCC.…”

Current status and contemporary approaches to the discovery of antitumor agents from higher plants

“…Mechanistically, americanin A induced G 2 /M cell cycle arrest followed by apoptosis. The same investigators further examined the mechanism of action, with the ATM/ATR signaling pathways and Skp2-p27 modulated, leading to a low micromolar cytotoxic activity (Jung et al, 2015). Another bioactive noni constituent is 2-methoxy-1,3,6-trihydroxyanthraquinone (Figure 4, 36), which in a quinone reductase (QR) in vitro assay showed a lack of cytotoxicity and 40fold increased activity on comparison with the positive control, ʟ-sulforaphane .…”

Antitumor Activity of Asperphenin A, a Lipopeptidyl Benzophenone from Marine-Derived Aspergillus sp. Fungus, by Inhibiting Tubulin Polymerization in Colon Cancer Cells

“…Cells were cultured in medium (DMEM for RKO, SK-HEP-1, and MDA-MB-231 cells; RPMI 1640 for SNU-638 cells) supplemented with 10% FBS and antibiotics-antimycotics (PSF; 100 units/mL penicillin G sodium, 100 µg/mL streptomycin, and 250 ng/mL amphotericin B) at 37 • C and 5% CO 2 in a humidified atmosphere. Cells were seeded at a density of 3-7 × 10 4 cells/mL in 96-well culture plates, and then treated with indicated compounds for 72 h. At the end of the experiment, cells were fixed with 10% TCA solution and subjected to sulforhodamine B (SRB) assay to determine cell proliferation [36]. The percentage of cell proliferation was calculated with the following formula:…”