gambogic-acid and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Chronic myeloid leukemia (CML) is a malignant disease of the hematopoietic system with crucial pathogenic protein named BCR-ABL, which endangers the life of patients severely. As a milestone of targeted drug, Imatinib has achieved great success in the treatment of CML. Nevertheless, inevitable drug resistance of Imatinib has occurred frequently in clinical due to the several mutations in the BCR-ABL kinase. Subsequently, the second-generation of tyrosine kinase inhibitors (TKIs) against BCR-ABL was developed to address the mutants of Imatinib resistance, except T315I. To date, the third-generation of TKIs targeting T315I has been developed for improving the selectivity and safety. Notably, the first allosteric inhibitor has been in market which could overcome the mutations in ATP binding site effectively. Meanwhile, some advanced technology, such as proteolysis-targeting chimeras (PROTAC) based on different E3 ligand, are highly expected to overcome the drug resistance by selectively degrading the targeted proteins. In this review, we summarized the current research progress of inhibitors and degraders targeting BCR-ABL for the treatment of CML.

Topics: Antineoplastic Agents; Benzamides; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Piperazines; Protein Kinase Inhibitors; Pyrimidines

This study was aimed to detect the effects of gambogic acid (GA) on the growth of chronic myelogenous leukemia (CML) K562 cells. Our results showed that GA induced the accumulation of autophagic vacuoles and up-regulation of two autophagy-related proteins (Beclin 1 and LC3). GA also induced down-regulation of mRNA levels of BCR-ABL fusion gene and SQSTM1/sequestosome 1 (p62) protein levels. After treatment by chloroquine (CQ) and pan caspase inhibitor Z-VAD-FMK (PC), both GA-induced autophagy and apoptosis were inhibited. Our study demonstrates that GA may induce cell death through autophagy and apoptosis pathways in CML K562 cells. A cross-talk mechanism exists between GA-induced autophagy and apoptosis. However, the mechanism of GA for inducing autophagy and apoptosis need further clarification.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Biomarkers; Cell Line, Tumor; Cell Survival; Fusion Proteins, bcr-abl; Gene Expression; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Xanthones

Chronic myelogenous leukemia (CML) is characterized by the constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl-T315I is the predominant mutation that causes resistance to imatinib, cytotoxic drugs, and the second-generation tyrosine kinase inhibitors. The emergence of imatinib resistance in patients with CML leads to searching for novel approaches to the treatment of CML. Gambogic acid, a small molecule derived from Chinese herb gamboges, has been approved for phase II clinical trial for cancer therapy by the Chinese Food and Drug Administration (FDA). In this study, we investigated the effect of gambogic acid on cell survival or apoptosis in CML cells bearing Bcr-Abl-T315I or wild-type Bcr-Abl.. CML cell lines (KBM5, KBM5-T315I, and K562), primary cells from patients with CML with clinical resistance to imatinib, and normal monocytes from healthy volunteers were treated with gambogic acid, imatinib, or their combination, followed by measuring the effects on cell growth, apoptosis, and signal pathways. The in vivo antitumor activity of gambogic acid and its combination with imatinib was also assessed with nude xenografts.. Gambogic acid induced apoptosis and cell proliferation inhibition in CML cells and inhibited the growth of imatinib-resistant Bcr-Abl-T315I xenografts in nude mice. Our data suggest that GA-induced proteasome inhibition is required for caspase activation in both imatinib-resistant and -sensitive CML cells, and caspase activation is required for gambogic acid-induced Bcr-Abl downregulation and apoptotic cell death.. These findings suggest an alternative strategy to overcome imatinib resistance by enhancing Bcr-Abl downregulation with the medicinal compound gambogic acid, which may have great clinical significance in imatinib-resistant cancer therapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Benzamides; Caspases; Cell Proliferation; Down-Regulation; Drug Resistance, Neoplasm; Enzyme Activation; Female; Fusion Proteins, bcr-abl; Gene Expression Regulation, Leukemic; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Monocytes; Piperazines; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrimidines; Xanthones; Xenograft Model Antitumor Assays