gambogic-acid and Hematologic-Neoplasms

Naturally occurring molecules derived from higher plants, animals, microorganisms and minerals play an important role in the discovery and development of novel therapeutic agents. The identification of molecular targets is of interest to elucidate the mode of action of these compounds, and it may be employed to set up target-based assays and allow structure-activity relationship studies to guide medicinal chemistry efforts toward lead optimization. In recent years, plant-derived natural compounds possessing potential anti-tumor activities have been garnering much interest and efforts are underway to identify their molecular targets. Here, we attempt to summarize the discoveries of several natural compounds with activities against hematological malignancies, such as adenanthin, oridonin, gambogic acid and wogonoside, the identification of their targets, and their modes of actions.

Topics: Biological Products; Diterpenes, Kaurane; Flavanones; Glucosides; Hematologic Neoplasms; Humans; Molecular Structure; Molecular Targeted Therapy; Phytotherapy; Xanthones

Gambogic acid (GA) is the main active ingredient of gamboge, a brownish to orange dry resin secreted from Garcinia hanburyi, a plant that is widely distributed in nature. Recent in vitro and in vivo studies have demonstrated that GA exerts potent antitumor effects against solid tumors of various derivations, and its antitumor mechanisms have been thoroughly investigated. On the other hand, normal cells remain relatively resistant to GA, indicating a therapeutic window. GA is currently in clinical trials in China. Over the last decade, our laboratory demonstrates that GA exhibits potent anticancer activities against hematological malignancies. This review focuses on the new mechanisms through which GA inhibits proliferation and induces apoptosis in malignant hematological cells. These include the regulation of expression and intracellular positioning of nucleoporin and nucleophosmin; downregulation of steroid receptor coactivator-3 (SRC-3) and its downstream proteins; upregulation of death inducer-obliterator (DIO-1); downregulation of HERG potassium channel; as well as induction of reactive oxygen species (ROS) accumulation.

Topics: Animals; Antineoplastic Agents, Phytogenic; DNA-Binding Proteins; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Garcinia; Hematologic Neoplasms; Humans; Nuclear Pore Complex Proteins; Nuclear Proteins; Nuclear Receptor Coactivator 3; Nucleophosmin; Reactive Oxygen Species; Xanthones

The human transferrin receptor (hTfR) is a target for cancer immunotherapy due to its overexpression on the surface of cancer cells. We previously developed an antibody-avidin fusion protein that targets hTfR (anti-hTfR IgG3-Av) and exhibits intrinsic cytotoxicity against certain malignant cells. Gambogic acid (GA), a drug that also binds hTfR, induces cytotoxicity in several malignant cell lines. We now report that anti-hTfR IgG3-Av and GA induce cytotoxicity in a new broader panel of hematopoietic malignant cell lines. Our results show that the effect of anti-hTfR IgG3-Av is iron-dependent whereas that of GA is iron-independent in all cells tested. In addition, we observed that GA exerts a TfR-independent cytotoxicity. We also found that GA increases the generation of reactive oxygen species that may play a role in the cytotoxicity induced by this drug. Additive cytotoxicity was observed by simultaneous combination treatment with these drugs and synergy by using anti-hTfR IgG3-Av as a chemosensitizing agent. In addition, we found a concentration of GA that is toxic to malignant hematopoietic cells but not to human hematopoietic progenitor cells. Our results suggest that these two compounds may be effective, alone or in combination, for the treatment of human hematopoietic malignancies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Avidin; Cell Line, Tumor; Drug Evaluation, Preclinical; Drug Synergism; Hematologic Neoplasms; Humans; Immunoglobulin G; Iron; Reactive Oxygen Species; Receptors, Transferrin; Recombinant Fusion Proteins; Xanthones