Triptolide inhibits the proliferation of cells from lymphocytic leukemic cell lines in association with downregulation of NF-κB activity and miR-16-1*

Abstract

Aim: To examine the effects of triptolide (TPL) on T-cell leukemia cells and identify their underlying mechanisms. Methods: The cytotoxicity of TPL was assessed by MTT assay. Cell apoptosis was determined using annexin V and DAPI staining and analyzed by flow cytometry or fluorescence microscopy. The activation of caspase pathways and the expression of nuclear factor κB (NF-κB) p65 were examined by Western blotting. Differences in microRNA (miRNA) expression in Molt-4 and Jurkat cells before and after TPL treatment were identified using microarrays and real-time RT-PCR, respectively. Results: TPL 20−160 nmol/L treatment potently inhibited cell growth and induced apoptosis in T-cell lymphocytic leukemia cell lines. Molt-4 and Jurkat cells, however, were more sensitive to TPL than L428 and Raji cells. After 24 h of treatment, bortezomib abrogated the growth of Molt-4 and Jurkat cells with an IC 50 of 15.25 and 24.68 nmol/L, respectively. Using Molt-4 cells, we demonstrated that TPL 20−80 nmol/L inhibited the translocation of NF-κB p65 from the cytoplasm to the nucleus and that phosphorylated NF-κB p65 in nuclear extracts was down-regulated in a dose-dependent manner. Similar results were also seen in Jurkat cells but not in L428 cells, as these cells are resistant to TPL and bortezomib (a NF-κB inhibitor). Twenty-three miRNAs were differentially expressed after TPL treatment. Functional analysis revealed that TPL treatment could inhibit expression of miR-16-1* and that transfection of miR-16-1* led to significantly decreased apoptosis induced by TPL. Conclusion: Our in vitro studies suggest that TPL might be an effective therapeutic agent for treatment of T-cell lymphocytic leukemia and that its cytotoxic effects could be associated with inhibition of NF-κB and down-regulation of miR-16-1*.

Triptolide Inhibits Proliferation and Induces Apoptosis of Human Melanoma A375 Cells

“…It has been reported to have pharmacological and biochemical properties in the treatment of rheumatoid arthritis and several other autoimmune and inflammatory diseases, including immune complex nephritis and systemic lupus erythematosus (Lu et al, 2011). Besides, triptolide has been shown to have antitumor properties in a variety of human tumor cells via inhibiting cell proliferation and inducing apoptosis (Mujumdar et al, 2010;Meng et al, 2011;Wu et al, 2011). Despite the recognized potent antitumor activity of triptolide, our knowledge regarding its mechanisms of action is still limited.…”

LLDT-67 attenuates MPTP-induced neurotoxicity in mice by up-regulating NGF expression

“…Yu et al [14] also found that triptolide inhibits global transcription in cancer cells by induction of phosphorylation and subsequent proteasome-dependent degradation of RNA polymerase II (Rpb1), resulting in global gene transcription. Meanwhile triptolide's anti-proliferative and proapoptotic effects have been reported as being caused by the inhibition of nuclear factor-kappaB (NF-κB) and nuclear factor of activated T-cells-mediated (NFAT-mediated) transcription and the suppression of HSP70 expression [15][16][17] . In this report, we demonstrate for the first time that LLDT-67, a novel derivative of triptolide, has a potent and specific effect on the expression of NGF in astrocytes in vitro and in vivo, which suggests that LLDT-67 can potentially serve as a neuroprotective agent in the treatment of neurodegenerative diseases.…”

Drug resistance-related microRNAs in hematological malignancies: Translating basic evidence into therapeutic strategies

“…In addition, they demonstrated that As 2 O 3 reduced the expression of let-7d and miR-766 by degrading PML and inhibiting PML body recycling. In fact, accumulating evidence is revealing an important role of miRNAs not just in anticancer drug resistance but in drug action [47][48][49][50][51][52][53][54][55][56]. More importantly, these emerging data provide the basis for the study and development of novel therapeutic strategies targeting miRNAs in hematological malignancies.…”