benzofurans and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Chronic myelogenous leukemia (CML) is a hematological malignancy with increased proliferation of cells of the myeloid series. This can disrupt normal hematopoiesis. The 1-(2-(dimethylamino)acetyl)-rocaglaol (MQ-16) is a new synthetic flavagline compound that showed promising activity in chronic myeloid leukemia K562 cells. This study aims to analyze the underlying mechanisms of MQ-16 against CML.. Growth, cell cycle progression, and apoptosis were assessed in K562 cells following MQ-16 exposure by MTT assay and flow cytometry. The effect of MQ-16 on DNA strands between nucleosomes was examined by 1% agarose gel electrophoresis. PI3K/Akt/mTOR, JAK2/STAT3, and mitogen-activated protein kinase (MAPK) pathway-related proteins were detected in MQ-16-treated K562 cells by Western blot.. MQ-16 significantly inhibited the proliferation of K562 cells and arrested the cell cycle at the G2/M phase in a time- and concentration-dependent manner. MQ-16 induced mitochondria-dependent apoptosis by downregulating the anti-apoptotic proteins Bcl-2 and Bcl-xL and induced time- and concentration-dependent DNA fragmentation. In addition, MQ-16 affected the expression of PI3K/Akt/mTOR, JAK2/STAT3, and MAPK pathway-related proteins.. In summary, MQ-16 appears to be a promising chemotherapeutic drug for treating CML.

Topics: Apoptosis; Benzofurans; Cell Proliferation; Humans; Janus Kinase 2; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; STAT3 Transcription Factor; TOR Serine-Threonine Kinases

The identification of novel compounds modulating the expression/activity of molecular targets downstream to BCR-ABL could be a new approach in the treatment of chronic myeloid leukemias (CMLs) resistant to imatinib or other BCR-ABL-targeted molecules. Recently, we synthesized a new class of substituted 2-(3,4,5-trimethoxybenzoyl)-2-N,N-dimethylamino-benzo[b]furans, and among these 3-iodoacetylamino-6-methoxybenzofuran-2-yl(3,5-trimethoxyphenyl)methanone (TR120) showed marked cytotoxic activity in BCR-ABL-expressing cells. Interestingly, TR120 was more potent than imatinib in cell growth inhibition and apoptosis induction in both BCR-ABL-expressing K562 and KCL22 cells. Moreover, it showed antitumor activity in imatinib-resistant K562-R and KCL22-R cells at concentrations similar to those active in the respective sensitive cells. Further, TR120 induced a marked decrease in signal transducer and activator of transcription 5 (STAT5) expression in K562 cells. Consistent with this effect, it determined a block of cells in the G0-G1 phase of the cell cycle, a decrease in the level of cyclin D1, and a reduction in Bcl-xL expression; however, it did not cause modifications in the Bcl-2 level. Of interest, TR120 had synergistic effects when used in combination with imatinib in both sensitive and resistant cells. Considering that STAT5 is a BCR-ABL molecular target that plays a key role in the pathogenesis of CML as well as in BCR-ABL-mediated resistance to apoptosis, TR120 could potentially be a useful novel agent in the treatment of imatinib-resistant CML.

Topics: Antineoplastic Agents; Apoptosis; bcl-X Protein; Benzamides; Benzofurans; Benzophenones; Bone Marrow Cells; Cell Line, Tumor; Colony-Forming Units Assay; Cyclin D1; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Fusion Proteins, bcr-abl; G1 Phase; Gene Expression Regulation, Neoplastic; Genes, bcl-1; Genes, bcl-2; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Necrosis; Neoplasm Proteins; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Resting Phase, Cell Cycle; STAT5 Transcription Factor

With an increasing cancer rate worldwide, there is an urgent quest for the improvement of anticancer drugs. One of the main problems of present chemotherapy in treatment of tumor patients is the toxicity of drugs. Most of the existent anticancer drugs, unfortunately, attack also proliferating normal cells. In recent years, traditional Chinese herbal remedies have gradually gained considerable attention as a new source of anticancer drugs. Although their healing mechanisms are still largely unknown, some of the drugs have been used to help cancer patients fight their disease at reduced side effects compared to other treatments. In our study, we show that Rocaglamide (Roc), derived from the traditional Chinese medicinal plants Aglaia, induces apoptosis through the intrinsic death pathway in various human leukemia cell lines and in acute lymphoblastic leukemia, chronic myeloid leukemia and acute myeloid leukemia cells freshly isolated from patients. Investigation of the molecular mechanisms by which Roc kills tumors revealed that it induces a consistent activation of the stress-response mitogen-activated protein kinase (MAPK) p38 accompanied with a long-term suppression of the survival MAPK extracellular signal-regulated kinase. These events affect proapoptotic Bcl-2 family proteins leading to depolarization of the mitochondrial membrane potential and trigger caspase-mediated apoptosis involving caspase-9, -8, -3 and -2. Importantly, Roc shows no effects on MAPKs in normal lymphocytes and therefore has no or very low toxicity on healthy cells. Up to now, more than 50 different Roc derivatives have been isolated from Aglaia. Our study suggests that Roc derivatives may be promising candidates for the development of new drugs against hematologic malignancies.

Topics: Acute Disease; Antineoplastic Agents; Apoptosis; Benzofurans; Cell Line, Tumor; Drugs, Chinese Herbal; Humans; JNK Mitogen-Activated Protein Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tubulin