scholarly journals mTOR kinase inhibitor pp242 causes mitophagy terminated by apoptotic cell death in E1A-Ras transformed cells

Oncotarget ◽  
2015 ◽  
Vol 6 (42) ◽  
pp. 44905-44926 ◽  
Author(s):  
Serguei A. Gordeev ◽  
Tatiana V. Bykova ◽  
Svetlana G. Zubova ◽  
Olga A. Bystrova ◽  
Marina G. Martynova ◽  
...  
Keyword(s):  
Cell Death ◽  
Kinase Inhibitor ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Transformed Cells ◽  
Mtor Kinase

scholarly journals E2 Proteins from High- and Low-Risk Human Papillomavirus Types Differ in Their Ability To Bind p53 and Induce Apoptotic Cell Death

2006 ◽  
Vol 80 (9) ◽  
pp. 4580-4590 ◽  
Author(s):  
Joanna L. Parish ◽  
Anna Kowalczyk ◽  
Hsin-Tien Chen ◽  
Geraldine E. Roeder ◽  
Richard Sessions ◽  
...  
Keyword(s):  
Cell Death ◽  
High Risk ◽  
Apoptotic Cell ◽  
Human Papillomaviruses ◽  
Apoptotic Cell Death ◽  
Low Risk ◽  
Transformed Cells ◽  
E2 Protein ◽  
Induced Apoptosis ◽  
High Risk Hpv

ABSTRACT The E2 proteins from oncogenic (high-risk) human papillomaviruses (HPVs) can induce apoptotic cell death in both HPV-transformed and non-HPV-transformed cells. Here we show that the E2 proteins from HPV type 6 (HPV6) and HPV11, two nononcogenic (low-risk) HPV types, fail to induce apoptosis. Unlike the high-risk HPV16 E2 protein, these low-risk E2 proteins fail to bind p53 and fail to induce p53-dependent transcription activation. Interestingly, neither the ability of p53 to activate transcription nor the ability of p53 to bind DNA, are required for HPV16 E2-induced apoptosis in non-HPV-transformed cells. However, mutations that reduce the binding of the HPV16 E2 protein to p53 inhibit E2-induced apoptosis in non-HPV-transformed cells. In contrast, the interaction between HPV16 E2 and p53 is not required for this E2 protein to induce apoptosis in HPV-transformed cells. Thus, our data suggest that this high-risk HPV E2 protein induces apoptosis via two pathways. One pathway involves the binding of E2 to p53 and can operate in both HPV-transformed and non-HPV-transformed cells. The second pathway requires the binding of E2 to the viral genome and can only operate in HPV-transformed cells.

Targeting 14-3-3 Sensitizes Native and Mutant BCR-ABL to Inhibition with U0126, Rapamycin and Bcl-2 Inhibitor GX15-070.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2920-2920
Author(s):  
Shaozhong Dong ◽  
Sumin Kang ◽  
Sagar Lonial ◽  
Hanna Jean Khoury ◽  
Jean Viallet ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Chromosomal Abnormalities ◽  
Apoptotic Cell ◽  
Wide Spectrum ◽  
Combined Therapy ◽  
Combined Treatment ◽  
Apoptotic Cell Death ◽  
Myelogenous Leukemia ◽  
Transformed Cells

Abstract Recurring chromosomal abnormalities in human leukemias result in expression of a wide spectrum of constitutively activated fusion tyrosine kinases, including BCR-ABL associated with t(9;22)(q34;q22) chronic myelogenous leukemia (CML). Small molecule tyrosine kinase inhibitors, such as imatinib, are effective therapies for BCR-ABL-mediated human leukemias. However, clinical drug resistance occurs, which warrants development of alternative and/or complementary therapeutic strategies to target critical downstream signaling molecules. We recently demonstrated that disrupting 14-3-3/ligand association by a peptide-based 14-3-3 competitive antagonist, R18 induces significant apoptosis, partially through reactivation of AKT-inhibited pro-apoptotic FOXO3a in FGFR1 fusion transformed hematopoietic cells [Dong et al, Blood, 2007, 110(1):360–9]. Here we report that targeting 14-3-3 by R18 effectively induced significant apoptosis in Ba/F3 and K562 cells expressing BCR-ABL, through liberation and reactivation of FOXO3a, but not by affecting 14-3-3/BCR-ABL association or BCR-ABL kinase activity. In addition, co-immunoprecipitation experiments revealed that R18 was not able to disrupt 14-3-3/BAD association, suggesting a model that targeting 14-3-3 by R18 induces apoptosis in BCR-ABL transformed cells, at least in part, through liberation and reactivation of FOXO3a phosphorylated and inhibited by activated AKT, but not BAD inhibited by ERK. Thus, we hypothesize that targeting 14-3-3 by R18 may potentiate the inhibition of BCR-ABL transformed cells induced by blocking the parallel MEK1/ERK pathway, pro-survival Bcl-2 proteins, or other signaling effectors downstream of AKT. Indeed, R18 sensitized BCR-ABL transformed cells to inhibition with MEK1 inhibitor U0126, Bcl-2 inhibitor GX15-070, or mTOR inhibitor rapamycin, and the combined treatment of R18 with these anti-cancer reagents synergistically induced apoptotic cell death. Moreover, treatment of these reagents potentiates R18-induced reactivation of pro-apoptotic FOXO3a with enhanced expression of downstream transcription targets including p27kip1 and Bim1, suggesting a potential molecular mechanism of the combined therapy. Furthermore, R18 induced apoptotic cell death in cells expressing diverse imatinib-resistant BCR-ABL mutants, including T315I. This inhibition was enhanced by treatment of R18 in combination with U0126 and rapamycin. Together, our findings suggest a novel therapeutic strategy that targeting 14-3-3 may potentiate the effects of conventional therapy for BCR-ABL associated hematopoietic malignancies, and overcome drug-resistance.

scholarly journals Chemical Constituent Profiling of Phyllostachys heterocycla var. Pubescens with Selective Cytotoxic Polar Fraction through EGFR Inhibition in HepG2 Cells

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 940
Author(s):  
Reda F. A. Abdelhameed ◽  
Eman S. Habib ◽  
Ahmed K. Ibrahim ◽  
Koji Yamada ◽  
Maged S. Abdel-Kader ◽  
...  
Keyword(s):  
Cell Death ◽  
Hepg2 Cells ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Apoptotic Cell ◽  
Chemical Constituent ◽  
Apoptotic Cell Death ◽  
Egfr Inhibition ◽  
In Silico Studies ◽  
Phyllostachys Heterocycla

Different extracts of the Bamboo shoot skin Phyllostachys heterocycla var. pubescens were screened against panel of cancer cell lines and normal one. The cell viability results exhibited that the ethyl acetate extract showed the least vitality percentage of 2.14% of HepG2 cells. Accordingly, it was subjected to chromatographic separation, which resulted in the isolation of a new natural product; 7-hydroxy, 5-methoxy, methyl cinnamate (1), together with four known compounds. The structures of the pure isolated compounds were deduced based on different spectroscopic data. The new compound (1) was screened against the HepG2 and MCF-7 cells and showed IC50 values of 7.43 and 10.65 µM, respectively. It induced apoptotic cell death in HepG2 with total apoptotic cell death of 58.6% (12.44-fold) compared to 4.71% in control by arresting cell cycle progression at the G1 phase. Finally, compound 1 was validated as EGFR tyrosine kinase inhibitor in both enzymatic levels (IC50 = 98.65 nM compared to Erlotinib (IC50 = 78.65 nM). Finally, in silico studies of compound 1 through the molecular docking indicated its high binding affinity towards EGFR protein and the ADME pharmacokinetics indicated it as a drug-like.

KIOM-79 prevents apoptotic cell death and AGEs accumulation in the retina of diabetic db/db mice

Planta Medica ◽  
2007 ◽  
Vol 73 (09) ◽  
Author(s):  
YS Kim ◽  
EJ Sohn ◽  
HY Lee ◽  
CS Kim ◽  
YM Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death
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