Psoralen reverses docetaxel-induced multidrug resistance in A549/D16 human lung cancer cells lines

Chemotherapy is the recommended treatment for advanced-stage cancers. However, the emergence of multidrug resistance (MDR), the ability of cancer cells to become simultaneously resistant to different drugs, limits the efficacy of chemotherapy. Previous studies have shown that herbal medicine or natural food may be feasible for various cancers as potent chemopreventive drug. This study aims to explore the capablility of reversing the multidrug resistance of docetaxel (DOC)-resistant A549 cells (A549/D16) of psoralen and the underlying mechanisms. In this study, results showed that the cell viability of A549/D16 subline is decreased when treated with psoralen plus DOC, while psoralen has no effect on the cell proliferation on A549 and A549/D16 cells. Furthermore, mRNA and proteins levels of ABCB1 were decreased in the presence of psoralen, while decreased ABCB1 activity was also revealed by flow cytometry. Based on these results, we believe that psoralen may be feasible for reversing the multidrug resistance by inhibiting ABCB1 gene and protein expression. Such inhibition will lead to a decrease in ABCB1 activity and anti-cancer drug efflux, which eventually result in drug resistance reversal and therefore, sensitizing drug-resistant cells to death in combination with chemotherapeutic drugs.     

Cloning and sequencing of a plasmid-mediated erythromycin resistance determinant from Staphylococcus xylosus

A 2.3-kb DNA fragment cloned from plasmid pCH200, the largest (52 kb) of four plasmids detected in Staphylococcus xylosus, was found to confer resistance to 14-membered ring macrolides in Bacillus subtilis and Staphylococcus aureus. DNA-sequence analysis of the fragment revealed the presence of an open-reading frame, the deduced product of which was identical to one of the two ATP-binding domains encoded by the macrolide/streptogramin-B-resistance gene msrA of Staphylococcus epidermidis. The observation that a polypeptide homologous to the C-terminus of MsrA is capable of mediating erythromycin resistance in the absence of the N-terminal region is of significance both to the evolution and functional activity of members of the ATP-binding transport super-gene family.     

Signaling steps in the induction of genomic damage by insulin in colon and kidney cells

Diabetes mellitus (DM), a disease with almost 350 million people affected worldwide, will be the seventh leading cause of death by 2030. Diabetic patients develop various types of complications, among them an increased rate of malignancies. Studies reported the strong correlation between DM and several cancer types, of which colon and kidney cancers are the most common. Hyperinsulinemia, the high insulin blood level characteristic of early diabetes type 2, was identified as a risk factor for cancer development. In previous studies, we showed that an elevated insulin level can induce oxidative stress, resulting in DNA damage in colon cells in vitro and in kidney cells in vitro and in vivo. In the present study, we elucidate the signaling pathway of insulin-mediated genotoxicity, which is effective through oxidative stress induction in colon and kidney. The signaling mechanism is starting by phosphorylation of the insulin and insulin-like growth factor-1 receptors, followed by activation of phosphatidylinositide 3-kinase (PI3K), which in turn activates AKT. Subsequently, mitochondria and nicotinamide adenine dinucleotide phosphate oxidase (NADPH) isoforms (Nox1 and Nox4 in colon and kidney, respectively) are activated for reactive oxygen species (ROS) production, and the resulting excess ROS can attack the DNA, causing DNA oxidation. We conclude that hyperinsulinemia represents an important risk factor for cancer initiation or progression as well as a target for cancer prevention in diabetic patients.     

Cellular resistance to the antimelanoma immunotoxin ZME-gelonin and strategies to target resistant cells

 The development of cellular resistance to immunotoxins has been demonstrated in a variety of models and can involve a number of mechanisms. For the present study, an immunotoxin was utilized composed of an antimelanoma antibody ZME-018 recognizing a 240-kDa surface glycoprotein (gp 240) and the plant toxin gelonin. Human melanoma cells (A375-M) were grown in the presence of increasing amounts of ZME-gelonin and a clonal variant (A-375-ZR) was developed that was 100-fold resistant to ZME-gelonin compared to parental cells. Scatchard analysis showed that the A375-M parental cells had 260×10³ ZME-gelonin-binding sites/cell with relatively low affinity (5 nM). In contrast, resistant A375-ZR cells demonstrated a reduced number of low-affinity sites (160×10³/cell), but showed a small number (47×10³) of higher-affinity sites (0.8 nM). Internalization rates and degradation rates of ¹²⁵I-labeled ZME-gelonin were identical in both the parental and resistant cells. A375-ZR cells were found to be more resistant to vincristine and doxorubicin than were parental cells. Both cell lines were almost equally sensitive to native gelonin, 5-fluorouracil (5-FU), cisplatin, melphalan, carmustine, interferon γ (IFNγ) and IFNα. In addition, both cell lines were equally sensitive to another gelonin-antibody conjugate that binds to cell-surface, GD₂ (antibody 14G₂A). However, resistant cells were twice as sensitive to the cytotoxic effects of etoposide than were parental cells. Finally, a variety of agents were tested in combination with ZME-gelonin against A375-ZR cells in an attempt to identify agents to augment immunotoxin cytotoxic effects against resistant cells. The agents 5-FU, cisplatin, IFNγ, IFNα, and etoposide were the most effective in augmenting the cytotoxicity of ZME-gelonin against resistant cells. These studies suggest that development of resistance to one immunotoxin does not cause development of cross-resistance to other gelonin immunotoxins. Further, specific biological response modifiers and chemotherapeutic agents may be effective in augmenting the effectiveness of immunotoxins and specifically targeting or reducing the emergence of immunotoxin-resistant cells. Received: 15 March 1995 / Accepted: 28 November 1995     

Evolution of insecticide resistance in Culex pipiens populations: The Corsican paradox

Culex pipiens mosquitoes from Corsica have been subject to insecticide treatments since 1971, using temephos (an organophosphate). After 17 years, resistance has not developed beyond a 14-fold level. This relatively low resistance is due to the presence of several identified resistance genes, including the insensitive target ( Ace^R ) and overproduced esterases (A1, A4 and B4). The fact that only a low resistance has developed after 17 years of treatment and that this low resistance level is the result of a relatively large number of resistance genes constitute a paradox. To understand this situation and explain why a higher temephos resistance level has not evolved in Corsica as in other parts of the world, it is proposed that the occurrence (through mutation or migration) of efficient resistance genes was a limiting step, and that the only resistance genes available at that time through migration from the surrounding Mediterranean countries had a low cross-resistance to temephos. The local situation of Corsica is discussed in the light of recent data on the world distribution of the known organophosphate resistance genes in this species, and the relative role of mutation and migration in the evolution of insecticide resistance in natural populations.     

The ecology and evolution of induced responses to herbivory and how plants perceive risk

1. Plants perceive herbivore damage or increased risk and respond. These changes may increase plant fitness, although effects on fitness have often been assumed without supporting evidence. 2. Three models have been proposed to explain induced rather than constitutive defence. The optimal defence model posits that induction allow plants to reduce allocation costs; it predicts demonstrably lower costs when defences are not needed. The moving target model posits that induction increases spatial and temporal variability; it predicts that variability will be difficult for herbivores and will provide defence. The information transfer model posits that induced responses provide cues to other tissues on that individual plant and to other organisms in the community; it predicts that induced cues will provide systemic resistance, deter herbivores, and/or attract enemies of herbivores, thereby benefiting the induced plant. 3. All three models predict that cues must be reliable to be useful. In some cases, cues provide specific information about the damaged plant tissue and the herbivore and this specific information may allow plants to fine-tune responses. Recent theory posits that selection should favour plants that minimise recognition errors and reduce fitness costs associated with errors. 4. Future research should focus on exploring different modalities used by plants to perceive herbivore risk, the benefits and costs of perceiving cues and inducing resistance, and the basic natural history of these phenomena. Induced responses have great unrealised potential in agriculture, and research should focus on host plant resistance rather than attempting to involve other trophic levels.     

Cytoplasmic APE1 promotes resistance response in osteosarcoma patients with cisplatin treatment

Chemotherapy resistance has become a hold back and major clinical challenge in osteosarcoma cancer. The alteration and subcellular distribution of apurinic/apyrimidinic endonuclease 1 (APE1) has been reported to be involved in chemotherapy resistance in many cancers. Here, we report that the cytoplasmic distribution of APE1 plays a key role in the sensitivity of combination platinum chemotherapy in osteosarcoma. Interestingly, the prevalence of cisplatin-induced DNA damage and apoptosis in low cytoplasmic APE1 osteosarcoma cell lines was higher than in high expression of cytoplasmic APE1 cell lines. Overexpression of cytoplasmic APE1 protected the osteosarcoma cells from CDDP-induced apoptosis. In addition, clinical data also show that the level of cytoplasmic APE1 was negatively associated with sensitivity to combination chemotherapy of cisplatin in osteosarcoma patients. Our findings suggest that cytoplasmic APE1 plays a significant role in chemotherapy resistance. This role is a supplement to the extranuclear function of APE1, and cytoplasmic APE1 expression level could be a promising predictor of platinum treatment prognosis for osteosarcoma patients.     

Discovery of 4-hydroxy-2-oxo-1,2-dihydroquinolines as potential inhibitors of Streptococcus pneumoniae,including drug-resistant strains

New therapies for treating drug-resistant pneumococcal infections are urgently needed. The novel scaffold 6-hydroxy-4-oxo-1,2-dihydro-4H-quinoline was shown to have similar efficacies against all three different serotypes of S. pneumoniae, ATCC 49617™ (19F), ATCC BAA-1663™ (15B), and ATCC 700904™ (19A), in a resazurin-based high-throughput screen using the Korea Chemical Bank library. Further studies to identify a new lead with this scaffold, including tricyclic pyrrolo[3,2,1-ij]quinolone and pyrido[3,2,1-ij]quinolone derivatives, led to the identification of 6d, 7d and 12a. Compound 6d (IC₅₀ = 0.92, 0.75, and 0.77 µM), 7d (IC₅₀ = 0.57, 0.66, and 0.38 µM) and 12a (IC₅₀ = 0.27, 1.03, and 0.62 µM) showed submicromolar IC₅₀ values against 19F, 15B, and 19A, respectively, and thus serve as a starting point for further optimization. While some of compounds in this series exhibited acceptable pharmacokinetic profiles in preliminary in vivo rat experiments, the most active compound 12a showed poor solubility and high plasma protein binding. Our current research efforts are focused on optimizing compounds to improve physicochemical properties as well as potency.