naphthoquinones and triptolide

The proteasome is a multicatalytic protease complex whose activity is required for the growth of normal or tumor cells. It has been shown that human cancer cells are more sensitive to proteasome inhibition than normal cells, indicating that the proteasome could be a target of chemotherapy. Studies suggest that traditional Chinese medicine (TCM) is an effective approach for cancer treatment. Here we reviewed several TCMs for their potential in treatment of cancer. This short review focuses mainly on the TCMs that potentially target the tumor cellular proteasome and NF-kappaB pathway whose activation is dependent on the proteasome activity.

Topics: Animals; Antineoplastic Agents, Phytogenic; Benzyl Compounds; Curcumin; Diterpenes; Drug Delivery Systems; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; Epoxy Compounds; Humans; Medicine, Chinese Traditional; Molecular Structure; Naphthoquinones; Neoplasms; Pentacyclic Triterpenes; Phenanthrenes; Phenols; Proteasome Endopeptidase Complex; Signal Transduction; Triterpenes

Sarcomas are a heterogeneous group of mesenchymal orphan cancers and new treatment alternatives beyond traditional chemotherapeutic regimes are much needed. So far, tumor mutation analysis has not led to significant treatment advances, and we have attempted to bypass this limitation by performing direct drug testing of a library of 353 anti-cancer compounds that are either FDA-approved, in clinical trial, or in advanced stages of preclinical development on a panel of 13 liposarcoma cell lines. We identified and validated six drugs, targeting different mechanisms and with good efficiency across the cell lines: MLN2238 -a proteasome inhibitor, GSK2126458 -a PI3K/mTOR inhibitor, JNJ-26481585 -a histone deacetylase inhibitor, triptolide-a multi-target drug, YM155 -a survivin inhibitor, and APO866 (FK866)-a nicotinamide phosphoribosyl transferase inhibitor. GR50s for those drugs were mostly in the nanomolar range, and in many cases below 10 nM. These drugs had long-lasting effect upon drug withdrawal, limited toxicity to normal cells and good efficacy also against tumor explants. Finally, we identified potential genomic biomarkers of their efficacy. Being approved or in clinical trials, these drugs are promising candidates for liposarcoma treatment.

Topics: Acrylamides; Antineoplastic Agents; Biomarkers, Pharmacological; Boron Compounds; Cell Line, Tumor; Diterpenes; Drug Evaluation, Preclinical; Epoxy Compounds; Glycine; High-Throughput Screening Assays; Humans; Hydroxamic Acids; Imidazoles; Liposarcoma; Naphthoquinones; Phenanthrenes; Piperidines; Pyridazines; Quinolines; Small Molecule Libraries; Sulfonamides