Xiao-Yang Fan

Oxidative stress-mediated intrinsic apoptosis in human promyelocytic leukemia HL-60 cells induced by organic arsenicals

Arsenic trioxide has shown the excellent therapeutic efficiency for acute promyelocytic leukemia. Nowadays, more and more research focuses on the design of the arsenic drugs, especially organic arsenicals, and on the mechanism of the inducing cell death. Here we have synthesized some organic arsenicals with Schiff base structure, which showed a better antitumor activity for three different kinds of cancer cell lines, namely HL-60, SGC 7901 and MCF-7. Compound 2a (2-(((4-(oxoarsanyl)phenyl)imino)methyl)phenol) and 2b (2-methoxy-4-(((4-(oxoarsanyl)phenyl)imino)methyl)phenol) were chosen for further mechanism study due to their best inhibitory activities for HL-60 cells, of which the half inhibitory concentration (IC50) were 0.77 μM and 0.51 μM, respectively. It was illustrated that 2a or 2b primarily induced the elevation of reactive oxygen species, decrease of glutathione level, collapse of mitochondrial membrane potential, release of cytochrome c, activation of Caspase-3 and apoptosis, whereas all of the phenomena can be eliminated by the addition of antioxidants. Therefore, we concluded that compound 2a and 2b can induce the oxidative stress-mediated intrinsic apoptosis in HL-60 cells. Both the simplicity of structure with Schiff base group and the better anticancer efficiency demonstrate that organic arsenicals are worthy of further exploration as a class of potent antitumor drugs.

Resonance energy transfer, pH-induced folded states and the molecular interaction of human serum albumin and icariin.

Icariin is a flavonol glycoside with a wide range of pharmacological and biological activities. The pharmacological and biological functions of flavonoid compounds mainly originate from their binding to proteins. The mode of interaction of icariin with human serum albumin (HSA) has been characterized by fluorescence spectroscopy and far- and near-UV circular dichroism (CD) spectroscopy under different pH conditions. Fluorescence quenching studies showed that the binding affinity of icariin with HSA in the buffer solution at different pH values is: Ka (pH 4.5) > Ka (pH 3.5) > Ka (pH 9.0) > Ka (pH 7.0). Red-edge excitation shift (REES) studies revealed that pH had an obvious effect on the mobility of the tryptophan microenvironment and the addition of icariin made the REES effect more distinct. The static quenching mechanism and number of binding sites (n ≈ 1) were obtained from fluorescence data at three temperatures (298, 304 and 310 K). Both ∆H(0) < 0 and ∆Ѕ(0) < 0 suggested that hydrogen bonding and van der Waals interaction were major driving forces in the binding mechanism, and this was also confirmed by the molecular simulation results. The distance r between the donor (HSA) and the acceptor (icariin) was calculated based on Förster non-radiation energy transfer theory. We found that pH had little impact on the energy transfer between HSA and icariin. Far- and near-UV CD spectroscopy studies further indicated the influence of pH on the complexation process and the alteration in the protein conformation upon binding.

Conjugated 5-fluorouracil with mitochondria-targeting lipophilic cation: design, synthesis and biological evaluation

5-Fluorouracil (5-FU) was linked with F16 by vulnerable bonds to selectively target cancer mitochondria which resulted in conjugated compounds, including F16–5-FU, F16–OOC-FU, F16–NHOC-FU and F16–SS-FU. F16–OOC-FU decreased the antiproliferative activity of 5-FU on the nontumor cell line, and the cytotoxicity of F16–SS-FU significantly increased when administered with dithiothreitol (DTT).

Comprehensive Study of the Interaction Between a Potential Antiprion Cationic Porphyrin and Human Prion Protein at Different pH by Using Multiple Spectroscopic Methods

Cationic porphyrins are potential antiprion drugs; however, the action mechanisms remain poorly understood. Herein, the interaction between a cationic porphyrin and recombinant human prion protein (rPrP(C)) was comprehensively studied by using surface plasmon resonance (SPR), fluorescence, resonance light scattering (RLS), and circular dichroism (CD) spectroscopy. The experimental results showed that the interaction between the cationic porphyrin and rPrP(C) was pH dependent. The equilibrium association constants obtained from SPR spectroscopy were 4.12 × 10(3) M(-1) at pH 4.0, 1.74 × 10(5) M(-1) at pH 6.0, and 5.98 × 10(5) M(-1) at pH 7.0. The binding constants at 298 K obtained from the fluorescence quenching method were 7.286 × 10(4) M(-1) at pH 4.0 and 1.457 × 10(5) M(-1) at pH 6.0. The thermodynamic parameters such as enthalpy change, entropy change, and free energy change were calculated, and the results indicated hydrogen bonds and van der Waals interactions played a major role in the binding reaction. The RLS experiment was performed to study the influence of porphyrin on the rPrP(C) aggregation at different pH values. The CD experiments were conducted to investigate the effects of porphyrin on the secondary structure and thermal stability of rPrP(C). Finally, the comparison of SPR measurement and fluorescence quenching measurement was discussed.