Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Curcumin (1), a natural polyphenolic compound, has shown strong antioxidant and anticancer activities. Several molecular mechanisms have been attributed to its inhibitory effects on a wide range of tumor cells. In this study, the response of the chronic myeloid leukemia cell line K562 cells to 1 is investigated. Curcumin inhibited the viability of K562 cells in a dose- and time-dependent manner. Furthermore, curcumin-induced cell death was associated with the formation of the apoptosome complex, the collapse of the mitochondrial membrane potential, and caspase-3 activation. Curcumin treatment also induced Bid cleavage and downregulated the expression of Bcl-2 protein. Surprisingly, even with these molecular features of apoptosis, we showed that 1 stimulated autophagy, which was evidenced by microtubule-associated protein light chain 3 (LC3) immunoreactivty. Curcumin also increased the protein levels of beclin 1 and membrane form LC3 (LC3-II). Autophagy inhibitor bafilomycin A1 and the pan-caspase inhibitor Z-VAD-fmk suppressed curcumin-induced K562 cell death. Overall, these results suggest that curcumin induces autophagic and apoptotic death of K562 cells. These findings suggest that both apoptotic and autophagic mechanisms contribute to the curcumin-induced K562 cell death.
 ...
PMID:Autophagic and apoptotic mechanisms of curcumin-induced death in K562 cells. 2018 54

Diabetes mellitus (DM), a state of chronic hyperglycemia, is associated with a variety of serious complications. Hyperglycemia-induced advanced glycation end products (AGEs) play an important role in the development of diabetic complications. In vivo, we demonstrated that disrupted mitochondria and autophagy was elevated in type II DM db/db mice. Mitophagy was evidenced by increased autophagosome formation in the beta-islet cells. The adducts of N(epsilon)-(carboxymethyl) lysine (CML), a major AGE, and bovine serum albumin (CML-BSA) stimulated the conversion of microtubule-associated protein 1 light chain 3-I (LC3-I) to LC3-II in rat insulinoma cells (RIN-m5F). CML-BSA increased ROS generation as demonstrated in a time-dependent manner. Experiments with mitochondrial targeted enhanced yellow fluorescent protein transfected RIN-m5F cells, massive fragmented mitochondria were visualized in the CML-BSA treated cells. Taken together, these data suggested that AGEs may cause mitochondrial dysfunction and mitophagosome formation, and AGEs-induced glycoxidative stress may trigger mitophagic process to modulate mitochondrial fates leading to either cell survival or cell death.
 ...
PMID:Glycoxidative stress-induced mitophagy modulates mitochondrial fates. 2064 31

Hepatocellular carcinoma (HCC) is the most common liver cancer and the third-leading cause of cancer death worldwide. Nilotinib is an orally available receptor tyrosine kinase inhibitor approved for chronic myelogenous leukemia. This study investigated the effect of nilotinib on HCC. Nilotinib did not induce cellular apoptosis. Instead, staining with acridine orange and microtubule-associated protein 1 light chain 3 revealed that nilotinib induced autophagy in a dose- and time-dependent manner in HCC cell lines, including PLC5, Huh-7, and Hep3B. Moreover, nilotinib up-regulated the phosphryaltion of AMP-activated kinase (AMPK) and protein phosphatase PP2A inactivation were detected after nilotinib treatment. Up-regulating PP2A activity suppressed nilotinib-induced AMPK phosphorylation and autophagy, suggesting that PP2A mediates the effect of nilotinib on AMPK phosphorylation and autophagy. Our data indicate that nilotinib-induced AMPK activation is mediated by PP2A, and AMPK activation and subsequent autophagy might be a major mechanism of action of nilotinib. Growth of PLC5 tumor xenografts in BALB/c nude mice was inhibited by daily oral treatment with nilotinib. Western blot analysis showed both increased phospho-AMPK expression and decreased PP2A activity in vivo. Together, our results reveal that nilotinib induces autophagy, but not apoptosis in HCC, and that the autophagy-inducing activity is associated with PP2A-regulated AMPK phosphorylation.
...
PMID:Nilotinib induces autophagy in hepatocellular carcinoma through AMPK activation. 2367 89

The antitumor enzyme asparaginase, which targets essential amino acid L-asparagine and catalyzes it to L-aspartic acid and ammonia, has been used for years in the treatment of acute lymphoblastic leukemia (ALL), subtypes of myeloid leukemia and T-cell lymphomas, whereas the anti-chronic myeloid leukemia (CML) effect of asparaginase and its underlying mechanism has not been completely elucidated. We have shown here that asparaginase induced significant growth inhibition and apoptosis in K562 and KU812 cells. Apart from induction of apoptosis, we reported for the first time that asparaginase induced autophagic response in K562 and KU812 cells as evidenced by the formation of autophagosome, microtubule-associated protein light chain 3 (LC3)-positive autophagy-like vacuoles, and the upregulation of LC3-II. Further study suggested that the Akt/mTOR (mammalian target of rapamycin) and Erk (extracellular signal-regulated kinase) signaling pathway were involved in asparaginase-induced autophagy in K562 cells. Moreover, blocking autophagy using pharmacological inhibitors LY294002, chloroquine (CQ) and quinacrine (QN) enhanced asparaginase-induced cell death and apoptosis, indicating the cytoprotective role of autophagy in asparaginase-treated K562 and KU812 cells. Together, these findings provide a rationale that combination of asparaginase anticancer activity and autophagic inhibition might be a promising new therapeutic strategy for CML.
...
PMID:Asparaginase induces apoptosis and cytoprotective autophagy in chronic myeloid leukemia cells. 2573 56

Development of drug resistance due to BCR-ABL point mutations and the persistence of leukemia initiating cells has become a major obstacle for tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML). The BCR-ABL protein is an important client protein of heat shock protein 90 (Hsp90). BIIB021, an orally available Hsp90 inhibitor, has activity against various cancer cells. However, little is known about the inhibitory effect of BIIB021 on CML cells. We evaluated the inhibitory effects of BIIB021 on K562, K562/G (an imatinib-resistant cell lines), as well as 32D mouse leukemic cells expressing wild-type BCR-ABL (b3a2, 32Dp210) and T315I mutant BCR-ABL (32Dp210-T315I) cells. Our data showed that BIIB021 induced significant growth inhibition and apoptosis that was predominantly mediated by the mitochondrial pathway. BIIB021 also resulted in proteasomal degradation of BCR-ABL proteins. In addition to induction of apoptosis, we report for the first time that BIIB021 induced autophagic response as evidenced by the formation of autophagosome, increased conversion of microtubule-associated protein light chain 3 (LC3)-I to LC3-II, decreased p62 (SQSTM1) protein levels. Further study suggested that Akt-mTOR-Ulk1 signaling pathway was involved in BIIB021-triggered autophagy. Moreover, blocking autophagy using pharmacological inhibitor 3-methyladenine and bafilomycin A1 significantly enhanced cell death and apoptosis induced by BIIB021, indicating the cytoprotective role of autophagy in BIIB021-treated CML cells. Collectively, these data provide possible molecular mechanisms for the antileukemic effect of BIIB021 on imatinib-sensitive and -resistant CML cells and provide new insights into the future application of BIIB021 in the clinical treatment of CML.
 ...
PMID:Hsp90 inhibitor, BIIB021, induces apoptosis and autophagy by regulating mTOR-Ulk1 pathway in imatinib-sensitive and -resistant chronic myeloid leukemia cells. 2689 93