Expression of EGFR isoform D is regulated by HER receptor activators in breast cancer cells.

Human epidermal growth factor receptor isoform D (EGFR; isoform D) is a soluble protein from a 3 kb alternate mRNA transcript that arises from the human EGFR gene. Several studies have identified this circulating isoform of EGFR as a potential diagnostic biomarker for the detection of early stage of cancers. While the expression of the full-length EGFR (isoform A) is regulated by its cognate ligand, EGF, as well as by phorbol myristate acetate (PMA), no studies have examined the factors regulating the expression of EGFR isoform D.

Targeted Drug Delivery Biopolymers Effectively Inhibit Breast Tumor Growth and Prevent Doxorubicin-Induced Cardiotoxicity.

The anticancer agent doxorubicin(dox) has been widely used in the treatment of a variety of hematological malignancies and solid tumors. Despite doxorubicin's efficiency in killing tumor cells, severe damage to healthy tissues, along with cardiotoxicity, limits its clinical use. To overcome these adverse side effects, improve patient safety, and enhance therapeutic efficacy, we have designed a thermally responsive biopolymer doxorubicin carrier that can be specifically targeted to tumor tissue by locally applying mild hyperthermia (41 °C).

Cell-Penetrating Doxorubicin Released from Elastin-Like Polypeptide Kills Doxorubicin-Resistant Cancer Cells in In Vitro Study.

Elastin-like polypeptides (ELPs) undergo a characteristic phase transition in response to ambient temperature. Therefore, it has been be used as a thermosensitive vector for the delivery of chemotherapy agents since it can be used to target hyperthermic tumors. This novel strategy introduces unprecedented options for treating cancer with fewer concerns about side effects.

Current strategies for therapeutic drug delivery after traumatic CNS injury.

Therapeutic strategies for traumatic injuries in the central nervous system (CNS) are largely limited to the efficiency of drug delivery. Despite the disrupted blood-CNS barrier during the early phase after injury, the drug administration faces a variety of obstacles derived from homeostatic imbalance at the injury site. In the late phase after CNS injury, the restoration of the blood-CNS barrier integrity varies depending on the injury severity resulting in inconsistent delivery of therapeutics.

Elastin-Like Polypeptide Delivers a Notch Inhibitory Peptide to Inhibit Tumor Growth in Combination with Paclitaxel.

This research describes a thermally responsive elastin-like polypeptide (ELP) for the delivery of dnMAML peptides that inhibit the Notch pathway. Exploiting passive targeting and a thermally active tumor-targeting technique available through the use of ELP, the dnMAML peptide was efficiently delivered to tumor tissue. Furthermore, this ELP-dnMAML was modified with the addition of a cell penetrating peptide (SynB1) for improved infiltration of ELP-dnMAML into the tumor cells.

Effects of cell penetrating Notch inhibitory peptide conjugated to elastin-like polypeptide on glioblastoma cells.

Notch pathway was found to be activated in most glioblastomas (GBMs), underlining the importance of Notch in formation and recurrence of GBM. In this study, a Notch inhibitory peptide, dominant negative MAML (dnMAML), was conjugated to elastin-like polypeptide (ELP) for tumor targeted delivery. ELP is a thermally responsive polypeptide that can be actively and passively targeted to the tumor site by localized application of hyperthermia.

Long-term exposures to low doses of silver nanoparticles enhanced in vitro malignant cell transformation in non-tumorigenic BEAS-2B cells.

To predict carcinogenic potential of AgNPs on the respiratory system, BEAS-2B cells (human bronchial epithelial cells) were chronically exposed to low- and non-cytotoxic dose (0.13 and 1.33μg/ml) of AgNPs for 4months (#40 passages).

Polymer-Based Prodrugs: Improving Tumor Targeting and the Solubility of Small Molecule Drugs in Cancer Therapy.

The majority of anticancer drugs have poor aqueous solubility, produce adverse effects in healthy tissue, and thus impose major limitations on both clinical efficacy and therapeutic safety of cancer chemotherapy. To help circumvent problems associated with solubility, most cancer drugs are now formulated with co-solubilizers. However, these agents often also introduce severe side effects, thereby restricting effective treatment and patient quality of life.

Cell-penetrating peptides: strategies for anticancer treatment.

Cell-penetrating peptides (CPP) provide an efficient strategy for the intracellular delivery of bioactive molecules in various biomedical applications. This review focuses on recent advances in the use of CPPs to deliver anticancer therapeutics and imaging reagents to cancer cells, along with CPP contributions to novel tumor-targeting techniques. CPPs are now used extensively to deliver a variety of therapeutics, despite lacking cell specificity and having a short duration of action.

Elastin-like polypeptide for improved drug delivery for anticancer therapy: preclinical studies and future applications.

Introduction: Despite their poor specificity, small molecule drugs are considered more powerful and effective than other current chemotherapies. A promising method for targeting these anticancer drugs to tumors, elastin-like polypeptides (ELP), has recently emerged. When an anticancer drug that has been conjugated to an ELP is administered, and focal hyperthermia applied, the thermoresponsive properties and enhanced permeability and retention effects of the ELP facilitate drug aggregation within tumor tissues.

Fusion of cell-penetrating peptides to thermally responsive biopolymer improves tumor accumulation of p21 peptide in a mouse model of pancreatic cancer.

Current therapies for the treatment of pancreatic cancer are limited. The limitations of this type of treatment are abundant. The majority of chemotherapeutic agents used in clinics are highly toxic to both tumor cells and normal tissues due to the lack of specificity.

Elastin-like polypeptides: the influence of its molecular weight on local hyperthermia-induced tumor accumulation.

Elastin-like polypeptides (ELP) are thermally responsive polypeptides that are soluble in solutions at 37°C, but which aggregate above 42°C. ELP can be used as effective carrier systems of anticancer molecules, because they can be targeted to tumor sites through the application of local hyperthermia. Since molecular size largely influences how successfully therapeutic agents can cross the vasculatures of tumors, it was crucial to determine an optimal molecular size.

Penetrating the cell membrane, thermal targeting and novel anticancer drugs: the development of thermally targeted, elastin-like polypeptide cancer therapeutics.

Therapeutic peptides offer important cancer treatment approaches. Designed to inhibit oncogenes and other oncoproteins, early therapeutic peptides applications were hampered by pharmacokinetic properties now addressed through tumor targeting strategies. Active targeting with environmentally responsive biopolymers or macromolecules enhances therapeutics accumulation at tumor sites; passive targeting with macromolecules, or liposomes, exploits angiogenesis and poor lymphatic drainage to preferentially accumulate therapeutics within tumors.

Anti-tumor efficacy of a therapeutic peptide based on thermo-responsive elastin-like polypeptide in combination with gemcitabine.

This work describes the effects of elastin-like polypeptide (ELP) with the p21(Waf1/Cip1)-derived cell cycle inhibitory peptide (p21) on pancreatic tumor cells with gemcitabine. The thermo-responsive property of ELP permits use of a mild, local hyperthermia to target tumors for the transport of chemotherapeutics. In this study, a p21-ELP construct with Bac cell penetrating peptide was designed, and its anticancer activities in pancreatic cancer cell lines was examined.

UVB-activated indole-3-acetic acid induces apoptosis of PC-3 prostate cancer cells.

Indole-3-acetic acid (IAA) has recently shown anticancer activity in combination with horseradish peroxidase. The current study demonstrated that IAA irradiated with ultraviolet B (IAA(UVB)) is able to generate free radicals and induce cell death in a time-dependent fashion in PC-3 prostate cancer cells, while PC-3 cells treated with IAA alone exhibited no toxic responses. It was also found through Western blot analysis that the cytotoxic effect of IAA(UVB) resulted from apoptosis.

Relaxation effect of synthetic ceramide analogues in cat esophageal smooth muscle cells.

Ceramide has emerged as a novel second messenger for intracellular signalling. It is produced from sphingomyelin and is involved in the control of cell differntiation, proliferation, and apoptosis. C(2)-ceramide, short chain ceramide, plays a role in mediating contraction of cat esophageal smooth muscle cells.

Synthesis and anticancer activity of geldanamycin derivatives derived from biosynthetically generated metabolites.

A new series of geldanamycin derivatives were synthesized using a semi-synthetic approach involving genetically engineered biosynthetic intermediates. These analogues were then evaluated for anti-proliferation activity in human cancer cell lines, SK-Br3 and SK-Ov3. Most of the synthesized compounds exhibited potent in vitro anti-proliferation activity toward both cell lines.

Effect of hydrogen peroxide on VIP-induced relaxation of the cat lower esophageal sphincter.

We investigated the effects of hydrogen peroxide (H2O2) on relaxation of the cat lower esophageal sphincter (LES). Vasoactive intestinal peptide (VIP) caused dose-dependent relaxation of LES, and H2O2 reduced VIP-induced relaxation. Relaxation was also attenuated by pertussis toxin (PTX), indicating a Gi/o component.

Apoptosis induced by ID6105, a new anthracycline (11-hydroxyaclacinomycin X, Hyrubicin), and its anti-tumor effects on experimental tumor models.

A new anthracycline ID6105 (11-hydroxyaclacinomycin X, Hyrubicin), which has potent antitumor activities against a broad range of cancer cell lines, was produced by hybrid biosynthetic approach. We investigated ID6105-induced apoptosis and in vivo efficacy on experimental tumors, and also defined its optimal dosing schedule. From PARP cleavage assay and caspase-3 activation assay, we found that ID6105 can induce apoptosis in tumor cells and its ability was superior to doxorubicin.

Synthesis and biological evaluation of 5-arylamino-6-chloro-1H-indazole-4,7-diones as inhibitors of protein kinase B/Akt.

A series of 5-arylamino-6-chloro-1H-indazole-4,7-diones were synthesized and evaluated for their inhibitory activity on protein kinase B/Akt. The compounds exhibited a potent Akt1 inhibitory activity. Further mechanistic study revealed that they might have dual inhibitory effects on both activity and phosphorylation of Akt1 in PC-3 tumor cell line.

Sphingosine 1-phosphate-induced signal transduction in cat esophagus smooth muscle cells.

We investigated the mechanism of contraction induced by S1P in esophageal smooth muscle cells. Western blot analysis demonstrated that S1P(1), S1P(2), S1P(3), and S1P(5) receptors existed in the cat esophagus. Only penetration of EDG-5 (S1P(2)) antibody into permeabilized cells inhibited S1P-induced contraction.

In vivo antitumor efficacy and cardiotoxicity of novel anthracycline ID6105 (11-hydroxy-aclacinomycin X, Hyrubicin).

Hybrid biosynthetic approach produced a new anthracycline ID6105 (11-hydroxyaclacinomycin X, Hyrubicin), which has potent antitumor activities against a broad range of cancer cell lines. Like other anthracyclines, ID6105 has the inhibitory effects on DNA synthesis as well as topoisomerase II. As preclinical studies of ID6105, we investigated ID6105's efficacy on human tumors, and cardiotoxicity.

Pharmacokinetics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after i.v. bolus multiple administration in rats.

We investigated the pharmacokinetics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after intravenous (i.v.) bolus administration at a multiple dose every 24 h for 5 days in rats.

HPLC analysis and pharmacokinetic characteristics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, in rats and beagle dogs.

We investigated the pharmacokinetic characteristics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after intravenous (i.v.) bolus administration in rats and beagle dogs.