Insights into the In Vitro Antitumor Mechanism of Action of a New Pyranoxanthone

Abstract

Naturally occurring xanthones have been documented as having antitumor properties, with some of them presently undergoing clinical trials. In an attempt to improve the biological activities of dihydroxyxanthones, prenylation and other molecular modifications were performed. All the compounds reduced viable cell number in a leukemia cell line K‐562, with the fused xanthone 3,4‐dihydro‐12‐hydroxy‐2,2‐dimethyl‐2H,6H‐pyrano[3,2‐b]xanthen‐6‐one (5) being the most potent. The pyranoxanthone 5 was particularly effective in additional leukemia cell lines (HL‐60 and BV‐173). Furthermore, the pyranoxanthone 5 decreased cellular proliferation and induced an S‐phase cell cycle arrest. In vitro, the pyranoxanthone 5 increased the percentage of apoptotic cells which was confirmed by an appropriate response at the protein level (e.g., PARP cleavage). Using a computer screening strategy based on the structure of several anti‐ and pro‐apoptotic proteins, it was verified that the pyranoxanthone 5 may block the binding of anti‐apoptotic Bcl‐xL to pro‐apoptotic Bad and Bim. The structure‐based screening revealed the pyranoxanthone 5 as a new scaffold that may guide the design of small molecules with better affinity profile for Bcl‐xL.

Clitocybe alexandri extract induces cell cycle arrest and apoptosis in a lung cancer cell line: Identification of phenolic acids with cytotoxic potential

“…After centrifugation cells were incubated with PI (5 µg/ml) and RNase A in PBS (100 µg/ml) for 30 min on ice (Vasconcelos et al, 2000;Palmeira et al, 2010). Induced apoptosis was assayed by the Human Annexin V-FITC/PI apoptosis Kit (Bender MedSystems, Vienna, Austria) according to the manufacturer's instructions (Queiroz et al, 2011).…”

Leccinum vulpinum Watling induces DNA damage, decreases cell proliferation and induces apoptosis on the human MCF-7 breast cancer cell line

“…Cell proliferation was analysed with the BrdU assay, according to the protocol previously described by Palmeira et al (2010). Briefly, cells were treated for 48 h …”

Development of noncytotoxic PLGA nanoparticles to improve the effect of a new inhibitor of p53–MDM2 interaction

“…3,4-Dihydro-12-hydroxy-2,2-dimethyl-2H,6Hpyrano[3,2-b]xanthen-6-one (1) was obtained by a previously described method (Palmeira et al, 2010) and showed a purity of 98.5% by HPLC-DAD. PLGA 50:50 (M W : 50,000-75,000 Da), Pluronic ® F-68, glucose, polyvinyl alcohol (PVA), 6-coumarin, Tween ® 80 and Span ® 80 were purchased from Sigma-Aldrich Química (Sintra, Portugal) and Mygliol ® 812 was purchased from Acofarma (Coimbra, Portugal).…”

“…Recently, a dihydropyranoxanthone, synthetized by some of us, 3,4-dihydro-12-hydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-one (1, Fig. 1), presented significant antiproliferative and apoptotic inducing effects (Paiva et al, 2012;Palmeira et al, 2010) in human tumor cell lines. Both ␣-mangostin (Leão et al, 2013a) and compound 1 (Leão et al, 2013b) were shown to be promising inhibitors of p53-MDM2 interaction, with compound 1 showing the highest inhibitory activity in a yeast target-based assay, mimicking the activity of known p53 activators.…”