Involvement of p38 MAPK in the Anticancer Activity of Cultivated Cordyceps militaris

2015 ◽  
Vol 43 (05) ◽  
pp. 1043-1057 ◽  
Author(s):  
Shang-Min Chou ◽  
Wan-Jung Lai ◽  
Tzuwen Hong ◽  
Sheng-Hong Tsai ◽  
Yen-Hsun Chen ◽  
...  
Keyword(s):  
Cell Death ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Leukemia Cell ◽  
Underlying Mechanism ◽  
Cordyceps Militaris ◽  
Parp Cleavage ◽  
Therapeutic Effects ◽  
Human Leukemia ◽  
Akt Inhibitor

Cordyceps militaris is a traditional Chinese medicine frequently used for tonic and therapeutic purposes. Reports from our laboratory and others have demonstrated that extracts of the cultivated fruiting bodies of C. militaris (CM) exhibit a potent cytotoxic effect against many cancer cell lines, especially human leukemia cells. Here, we further investigated the underlying mechanism through which CM is cytotoxic to cancer cells. The CM-mediated induction of PARP cleavage and its related DNA damage signal (γH2AX) was diminished by caspase inhibitor I. In contrast, a ROS scavenger failed to prevent CM-mediated leukemia cell death. Moreover, two signaling molecules, AKT and p38 MAPK, were activated during the course of apoptosis induction. Employing MTT analysis, we found that a p38 MAPK inhibitor but not an AKT inhibitor could rescue cells from CM-mediated cell death, as well as inhibit the cleavage of PARP, formation of apoptotic bodies and up-regulation of the γH2AX signal. These results suggest that CM-mediated leukemia cell death occurs through the activation of the p38 MAPK pathway, indicating its potential therapeutic effects against human leukemia.

Dequalinium induces human leukemia cell death by affecting the redox balance

2011 ◽  
Vol 35 (10) ◽  
pp. 1395-1401 ◽  
Author(s):  
Ana I. García-Pérez ◽  
Eva Galeano ◽  
Elena Nieto ◽  
Pilar Sancho
Keyword(s):  
Cell Death ◽  
Leukemia Cell ◽  
Redox Balance ◽  
Human Leukemia ◽  
Human Leukemia Cell

scholarly journals Transferrin-Bound Doxorubicin Enhances Apoptosis and DNA Damage through the Generation of Pro-Inflammatory Responses in Human Leukemia Cells

2020 ◽  
Vol 21 (24) ◽  
pp. 9390
Author(s):  
Monika Jedrzejczyk ◽  
Katarzyna Wisniewska ◽  
Katarzyna Dominika Kania ◽  
Agnieszka Marczak ◽  
Marzena Szwed
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Morphological Observation ◽  
Human Leukemia ◽  
Dependent Manner ◽  
Normal Peripheral Blood

Doxorubicin (DOX) is an effective antineoplastic drug against many solid tumors and hematological malignancies. However, the clinical use of DOX is limited, because of its unspecific mode of action. Since leukemia cells overexpress transferrin (Tf) receptors on their surface, we proposed doxorubicin–transferrin (DOX–Tf) conjugate as a new vehicle to increase drug concentration directly in cancer cells. The data obtained after experiments performed on K562 and CCRF-CEM human leukemia cell lines clearly indicate severe cytotoxic and genotoxic properties of the conjugate drug. On the other hand, normal peripheral blood mononuclear cells (PBMCs) were more resistant to DOX–Tf than to DOX. In comparison to free drug, we observed that Tf-bound DOX induced apoptosis in a TRAIL-dependent manner and caused DNA damage typical of programmed cell death. These fatal hallmarks of cell death were confirmed upon morphological observation of cells incubated with DOX or DOX–Tf. Studies of expression of TNF-α, IL-4, and IL-6 at the mRNA and protein levels revealed that the pro-inflammatory response plays an important role in the toxicity of the conjugate. Altogether, the results demonstrated here describe a mechanism of the antitumor activity of the DOX–Tf conjugate.

Disparate Mechanisms of Antifolate Resistance Provoked by Methotrexate and Its Metabolite 7-Hydroxymethotrexate in Leukemia Cells: Implications for Efficacy of Methotrexate Therapy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4369-4369
Author(s):  
Freidoun Albertioni ◽  
Gerrit Jansen ◽  
Kambiz Fotoohi ◽  
Yehuda G. Assaraf ◽  
Lilah Rothem ◽  
...  
Keyword(s):  
Cell Lines ◽  
Leukemia Cell ◽  
Parent Drug ◽  
Underlying Mechanism ◽  
Human Leukemia ◽  
Folylpolyglutamate Synthetase ◽  
Leukemia Cell Lines ◽  
Short Term Exposure ◽  
Extensive Metabolism ◽  
Antifolate Resistance

Abstract Methotrexate (MTX) is one of the leading drugs in the treatment of leukemia, but extensive metabolism to 7-hydroxymethotrexate (7-OHMTX) can limit its therapeutic efficacy. In this study we investigated whether 7-OHMTX itself can provoke antifolate resistance that may further disrupt MTX efficacy. For this purpose we developed resistance to 7-OHMTX as well as MTX in two human leukemia cell lines (CCRF-CEM and MOLT-4) by stepwise exposure to increasing concentrations of 7-OHMTX and MTX. Consequently, both leukemia cell lines displayed marked levels of resistance to 7-OHMTX (>10 fold) and MTX (>75 fold), respectively. The underlying mechanism of resistance in the MTX-exposed cells was a marked decrease (>10-fold) in reduced folate carrier (RFC)-mediated cellular uptake of MTX. This was associated with transcriptional silencing of the RFC gene in MTX-resistant CCRF-CEM cells. In contrast, the molecular basis for the resistance to 7-OHMTX was solely due to a marked decreased (> 95%) in folylpolyglutamate synthetase (FPGS) activity which conferred >100-fold MTX resistance upon a short term exposure to this drug. This is the first demonstration that 7-OHMTX can provoke distinct modalities of antifolate resistance as compared to the parent drug MTX.

Combination of Farnesyl Transferase Inhibitor (Tipifarnib) with Perifosine Induces Apoptosis through phos-PDK1 in Human Lymphoma and Leukemia Cell Lines.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1488-1488 ◽  
Author(s):  
Ebenezer David ◽  
Rajni Sinha ◽  
Claire Torre ◽  
Jonathan L. Kaufman ◽  
Sagar Lonial
Keyword(s):  
Cell Death ◽  
Western Blot ◽  
Cell Lines ◽  
Blot Analysis ◽  
Leukemia Cell ◽  
Human Leukemia ◽  
Targeted Agents ◽  
Leukemia Cell Lines ◽  
Targeted Agent ◽  
The Impact

Abstract Introduction: Novel agents as anti-cancer therapy are used in the setting of specific molecular abnormalities that provide a survival advantage for malignant cells. One such agent, tipifarnib, is theoretically targeted at Ras mutations which are present in a number of different human cancers. Our previous experience with the FTIs (David et al, in press Blood) has demonstrated that they are ideal agents to combine with other targeted agents. We have investigated the combination of the AKT inhibitor perifosine with tipifarnib in human leukemia and lymphoma cell lines with the hypothesis that the combination of 2 targeted agents will disrupt separate survival pathways and ultimately result in synergistic tumor cell death. Methods: In this study we used the human leukemia cell lines HL-60, Jurkat, and the lymphoma cell line HT. Western blot analysis was used to assess for the effect of either single agent perifosine, tipifarnib, or the combination on AKT, p-AKT, PDK-1, and caspase cleavage. Flow cytometry was utilized to assess for Annexin V staining following combination therapy. Results:Dose escalation studies demonstrated that doses of tipifarnib up to 5μm demonstrated a significant cell death in HL-60 and HT cells. Perifosine doses of 1–5uM also induced cell death in both HL-60 and HT cells. When apoptosis was assessed using western blot analysis of caspase 3 activity and cleavage, the combination of perifosine and tipifarnib demonstrated significant apoptosis using low doses of both agents. The apoptosis was associated with downregulation of phos-PDK1, with a resultant downregulation in p-AKT. The level of phos-PDK1 was completely inhibited in less than 24 hrs in both the HL-60 and HT cell lines in combination than when either agent was given alone. Conclusion: The combination of perifosine, and AKT targeted agent, with tipifarnib, a Ras targeted agent, appear to induce significant cell death in lymphoma and leukemia cell lines with rapid downregulation of p-AKT via the PDK-1 pathway. This apoptosis occurs in vitro using concentrations well below those that have been achieved in current clinical trials using these agents. Additional studies are being carried out to further delineate the mechanism of synergy as well as to further explore the impact of sequence of administration using this combination. Further studies are also planned to xplore the impact of the combination on primary human leukemia and lymphoma cells from the blood and bone marrow.

Chemopreventive Agent Resveratrol, a Natural Product Derived From Grapes, Triggers CD95 Signaling-Dependent Apoptosis in Human Tumor Cells

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 996-1002 ◽  
Author(s):  
Marie-Véronique Clément ◽  
Jayshreekumari L. Hirpara ◽  
Sanaul-Haq Chawdhury ◽  
Shazib Pervaiz
Keyword(s):  
Cell Death ◽  
Natural Product ◽  
Tumor Cells ◽  
Leukemia Cell ◽  
Human Tumor ◽  
Leukemia Cell Line ◽  
Human Leukemia ◽  
Resveratrol Treatment ◽  
Dose Dependent Increase ◽  
Dose Dependent

Resveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression on HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling dependent. On the contrary, resveratrol treatment of normal human peripheral blood lymphocytes (PBLs) does not affect cell survival for up to 72 hours, which correlates with the absence of a significant change in either CD95 or CD95L expression on treated PBLs. These data show specific involvement of the CD95-CD95L system in the anti-cancer activity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreventive activity. © 1998 by The American Society of Hematology.

Inhibition of the Cardiac p38-MAPK Pathway by SB203580 Delays Ischemic Cell Death

2000 ◽  
Vol 35 (3) ◽  
pp. 474-483 ◽  
Author(s):  
Miroslav Barancik ◽  
Patrik Htun ◽  
Claudia Strohm ◽  
Sven Kilian ◽  
Wolfgang Schaper
Keyword(s):  
Cell Death ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
P38 Mapk Pathway

Vaticanol C-Induced Cell Death Is Associated with Inhibition of Pro-Survival Signaling in HL60 Human Leukemia Cell Line

2005 ◽  
Vol 69 (2) ◽  
pp. 353-356 ◽  
Author(s):  
Kenji OHGUCHI ◽  
Yukihiro AKAO ◽  
Kenji MATSUMOTO ◽  
Toshiyuki TANAKA ◽  
Tetsuro ITO ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Line ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Human Leukemia ◽  
Human Leukemia Cell ◽  
Human Leukemia Cell Line ◽  
Survival Signaling

scholarly journals Naja atra Cardiotoxin 1 Induces the FasL/Fas Death Pathway in Human Leukemia Cells

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2073
Author(s):  
Jing-Ting Chiou ◽  
Liang-Jun Wang ◽  
Yuan-Chin Lee ◽  
Long-Sen Chang
Keyword(s):  
P38 Mapk ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Human Leukemia ◽  
U937 Cells ◽  
Fasl Expression ◽  
Mechanistic Pathway ◽  
Leukemia Cell Lines ◽  
Sirna Knockdown ◽  
Naja Atra

This study aimed to investigate the mechanistic pathway of Naja atra (Taiwan cobra) cardiotoxin 1 (CTX1)–induced death of leukemia cell lines U937 and HL-60. CTX1 increased cytoplasmic Ca2+ and reactive oxygen species (ROS) production, leading to the death of U937 cells. It was found that Ca2+-induced NOX4 upregulation promoted ROS-mediated p38 MAPK phosphorylation, which consequently induced c-Jun and ATF-2 phosphorylation. Using siRNA knockdown, activated c-Jun and ATF-2 were demonstrated to regulate the expression of Fas and FasL, respectively. Suppression of Ca2+-mediated NOX4 expression or ROS-mediated p38 MAPK activation increased the survival of U937 cells exposed to CTX1. FADD depletion abolished CTX1-induced cell death, caspase-8 activation, and t-Bid production, supporting the correlation between the Fas death pathway and CTX1-mediated cytotoxicity. Among the tested N. atra CTX isotoxins, only CTX1 induced Fas and FasL expression. Chemical modification studies revealed that intact Met residues were essential for the activity of CTX1 to upregulate Fas and FasL expression. Taken together, the data in this study indicate that CTX1 induces c-Jun-mediated Fas and ATF-2-mediated FasL transcription by the Ca2+/NOX4/ROS/p38 MAPK axis, thereby activating the Fas death pathway in U937 cells. Furthermore, CTX1 activates Fas/FasL death signaling in the leukemia cell line HL-60.

Chemopreventive Agent Resveratrol, a Natural Product Derived From Grapes, Triggers CD95 Signaling-Dependent Apoptosis in Human Tumor Cells

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 996-1002 ◽  
Author(s):  
Marie-Véronique Clément ◽  
Jayshreekumari L. Hirpara ◽  
Sanaul-Haq Chawdhury ◽  
Shazib Pervaiz
Keyword(s):  
Cell Death ◽  
Natural Product ◽  
Tumor Cells ◽  
Leukemia Cell ◽  
Human Tumor ◽  
Leukemia Cell Line ◽  
Human Leukemia ◽  
Resveratrol Treatment ◽  
Dose Dependent Increase ◽  
Dose Dependent

Abstract Resveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression on HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling dependent. On the contrary, resveratrol treatment of normal human peripheral blood lymphocytes (PBLs) does not affect cell survival for up to 72 hours, which correlates with the absence of a significant change in either CD95 or CD95L expression on treated PBLs. These data show specific involvement of the CD95-CD95L system in the anti-cancer activity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreventive activity. © 1998 by The American Society of Hematology.

Sign in / Sign up

Export Citation Format

Share Document