Gambogic Acid Induces Apoptosis in Imatinib-Resistant Chronic Myeloid Leukemia Cells via Inducing Proteasome Inhibition and Caspase-Dependent Bcr-Abl Downregulation

Abstract

Purpose 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. Experimental Design 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. Results 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. Conclusions 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.

Gambogic acid inhibits the growth of ovarian cancer tumors by regulating p65 activity

“…Previous studies have suggested that GA induces cell cycle arrest and apoptosis (7), inhibits the activity of telomerase, angiogenesis and tumor metastasis, and decreases resistance to multiple chemotherapy drugs (8,9). The effect of GA is thought to be highly selective, in one study it was found to induce apoptosis only in tumor cells (10). However, the mechanism of action of GA on tumor cells remains unclear.…”

Natural products against hematological malignancies and identification of their targets

“…Their results showed that GA gains the proteasomeinhibitory function after being metabolized by intracellular CYP2E1, that GA induced proteasome inhibition is a prerequisite for its cytotoxicity and anticancer action without off-target effects, and that the expression of the CYP2E1 gene is very high in tumor tissues but low in many normal tissues, and thus GA can produce tissue-specific proteasome inhibition and tumor-specific toxicity (Figure 2). Further, they showed that GA-induced proteasome inhibition and caspase activation are required for GA-induced BCR-ABL downregulation and cell apoptosis [71]. Judging by present reports, most current studies are mainly focused on finding tyrosine kinase inhibitors to either downregulate BCR-ABL transcription or inhibit its tyrosine kinase activity.…”

“…The emergence of imatinib resistance in patients with CML les to the search for novel approaches for its treatment. Liu's group [71] has investigated the antineoplastic effects of GA in CML cell lines, mononuclear cells from CML patients and in imatinib-resistant xenograft murine models. The results indicated that GA induces apoptosis together with cell proliferation inhibition in CML cells, including those cells harboring the BCR-ABL-T315I mutation, and primary mononuclear cells from CML patients resistant to imatinib.…”

Autophagy in photodynamic therapy

“…Pathways for induction of apoptosis have been identifiedintrinsic and extrinsic, one involving caspase-8 and the other involving Caspase-9 as the most apical caspase, which can activate effector caspase, such as Caspase-3, -6, -7. The effector caspases then cleave intracellular substrates, thereby important cellular processes are disabled and eventually cell death is caused [7][8][9].…”