Ascorbate (vitamin C) was an early, unorthodox therapy for cancer, with an outstanding safety profile and anecdotal clinical benefit. Because oral ascorbate was ineffective in two cancer clinical trials, ascorbate was abandoned by conventional oncology but continued to be used in complementary and alternative medicine. Recent studies provide rationale for reexamining ascorbate treatment. Because of marked pharmacokinetic differences, intravenous, but not oral, ascorbate produces millimolar concentrations both in blood and in tissues, killing cancer cells without harming normal tissues. In the interstitial fluid surrounding tumor cells, millimolar concentrations of ascorbate exert local pro-oxidant effects by mediating hydrogen peroxide (H(2)O(2)) formation, which kills cancer cells. We investigated downstream mechanisms of ascorbate-induced cell death. Data show that millimolar ascorbate, acting as a pro-oxidant, induced DNA damage and depleted cellular adenosine triphosphate (ATP), activated the ataxia telangiectasia mutated (ATM)/adenosine monophosphate-activated protein kinase (AMPK) pathway, and resulted in mammalian target of rapamycin (mTOR) inhibition and death in ovarian cancer cells. The combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced chemotherapy-associated toxicity in patients with ovarian cancer. On the basis of its potential benefit and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy is justified in larger clinical trials.

It is commonly observed that hydrophobic molecules alone cannot self-assemble into stable nanoparticles, requiring amphiphilic or ionic materials to support nanoparticle stability and function in vivo. We report herein newly self-assembled nanomedicines through entirely different mechanisms. We present proof-of-concept methodology and results in support of our hypothesis that disulfide-induced nanomedicines (DSINMs) are promoted and stabilized by the insertion of a single disulfide bond into hydrophobic molecules, in order to balance the competition between intermolecular forces involved in the self-assembly of nanomedicines. This hypothesis has been explored through diverse synthetic compounds, which include four first-line chemotherapy drugs (paclitaxel, doxorubicin, fluorouracil, and gemcitabine), two small-molecule natural products and their derivatives, as well as a fluorescent probe. Such an unprecedented and highly reproducible system has the potential to serve as a synthetic platform for a wide array of safe and effective therapeutic and diagnostic nanomedicine strategies.

Background: In rats, esophagogastroduodenal anastomosis (EGDA) without concomitant chemical carcinogen treatment leads to gastroesophageal reflux disease, multilayered epithelium (MLE, a presumed precursor in intestinal metaplasia), columnar-lined esophagus, dysplasia, and esophageal adenocarcinoma. Previously we have shown that columnar-lined esophagus in EGDA rats resembled human Barrett's esophagus (BE) in its morphology, mucin features and expression of differentiation markers (Lab. Invest. 2004;84:753-765). The purpose of this study was to compare the phenotype of rat MLE with human MLE, in order to gain insight into the nature of MLE and its potential role in the development of BE.

In order to understand the antifungal activity of some derivatives of sanguinarine (S) and chelerythrine (C) and their structure-activity relationships, sixteen derivatives of S and C were prepared and evaluated for in vitro antifungal activity against seven phytopathogenic fungi by the mycelial growth rate method. The results showed that S, C and their 6-alkoxy dihydro derivatives S1–S4, C1–C4 and 6-cyanodihydro derivatives S5, C5 showed significant antifungal activity at 100 µg/mL against all the tested fungi. For most tested fungi, the median effective concentrations of S, S1, C and C1 were in a range of 14–50 µg/mL. The structure-activity relationship showed that the C=N+ moiety was the determinant for the antifungal activity of S and C. S1–S5 and C1–C5 could be considered as the precursors of S and C, respectively. Thus, the present results strongly suggested that S and C or their derivatives S1–S5 and C1–C5 should be considered as good lead compounds or model molecules to develop new anti-phytopathogenic fungal agents.

Recently, nanomedicine without drug carriers has attracted many pharmacists' attention. A novel paclitaxel-s-s-paclitaxel (PTX-s-s-PTX) conjugate with high drug loading (∼78%, w/w) was synthesized by conjugating paclitaxel to paclitaxel by using disulfide linkage. The conjugate could self-assemble into uniform nanoparticles (NPs) with 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR) encapsulated within the core of PTX-s-s-PTX NPs for photothermal therapy (PTT). The DiR-loaded self-assembled nanoparticles (DSNs) had a mean diameter of about 150 nm and high stability in biological condition. A disulfide bond is utilized as a redox-responsive linkage to facilitate a rapid release of paclitaxel in tumor cells. DSNs indicated significant cytotoxicity as a result of the synergetic chemo-thermal therapy. DSNs were featured with excellent advantages, including high drug loading, redox-responsive releasing behavior of paclitaxel, capability of loading with photothermal agents, and combinational therapy with PTT. In such a potent nanosystem, prodrug and photothermal strategy are integrated into one system to facilitate the therapy efficiency.