scholarly journals Cytochrome c: Using Biological Insight toward Engineering an Optimized Anticancer Biodrug

Inorganics ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 83
Author(s):  
Louis J. Delinois ◽  
Omar De León-Vélez ◽  
Adriana Vázquez-Medina ◽  
Alondra Vélez-Cabrera ◽  
Amanda Marrero-Sánchez ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Therapeutic Potential ◽  
Life And Death ◽  
Transfer Protein ◽  
Cellular Life ◽  
Electron Transfer Protein ◽  
Biological Insight ◽  
Cyt C ◽  
Cancer Types ◽  
Induced Apoptosis

The heme protein cytochrome c (Cyt c) plays pivotal roles in cellular life and death processes. In the respiratory chain of mitochondria, it serves as an electron transfer protein, contributing to the proliferation of healthy cells. In the cell cytoplasm, it activates intrinsic apoptosis to terminate damaged cells. Insight into these mechanisms and the associated physicochemical properties and biomolecular interactions of Cyt c informs on the anticancer therapeutic potential of the protein, especially in its ability to subvert the current limitations of small molecule-based chemotherapy. In this review, we explore the development of Cyt c as an anticancer drug by identifying cancer types that would be receptive to the cytotoxicity of the protein and factors that can be finetuned to enhance its apoptotic potency. To this end, some information is obtained by characterizing known drugs that operate, in part, by triggering Cyt c induced apoptosis. The application of different smart drug delivery systems is surveyed to highlight important features for maintaining Cyt c stability and activity and improving its specificity for cancer cells and high drug payload release while recognizing the continuing limitations. This work serves to elucidate on the optimization of the strategies to translate Cyt c to the clinical market.

Androgen-Responsive Lncap and Androgen-Independent Du145 Prostate Cancer Cells Display Different Taxol Sensitivities

1999 ◽  
Vol 5 (S2) ◽  
pp. 1110-1111
Author(s):  
Maureen Ripple ◽  
Meghan Taylo ◽  
Chris Huese ◽  
Heide Schatte
Keyword(s):  
Prostate Cancer ◽  
Cytochrome C ◽  
Cancer Cells ◽  
Metastatic Breast ◽  
Prostate Cancer Cells ◽  
Obvious Effect ◽  
C Elegans ◽  
Transfer Protein ◽  
Electron Transfer Protein ◽  
Anti Cancer

Taxol has been used as anti-cancer compound against prostate, ovarian, and metastatic breast cancer. While the most obvious effect of taxol is bundeling of microtubules and mitotic arrest, recent studies have demonstrated that taxol is able to induce intranucleosomal DNA fragmentation and typical morphological features of apoptosis in a number of solid tumor cells. These results indicate that taxol may exert its anti-tumor effects via secondary mechanisms which may or may not be related to its primary effects on microtubules. It has been shown that taxol-induced microtubular changes and G2/M arrest are associated with the release of the electron transfer protein cytochrome C from mitochondria into the cytosol. Cytochrome C then binds to APAF-1 (a human homolog of the ced-4 gene of C. elegans), which binds, cleaves, and activates caspase- 9, ultimately resulting in the cleavage and activity of caspase-3. We investigated the effects of taxol (100nM) on microtubules, on DNA, and on the pre-apoptotic mitochondrial events using LNCaP and DU145 prostate cancer cells.

Mitochondrial phospholipid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis

2000 ◽  
Vol 351 (1) ◽  
pp. 183-193 ◽  
Author(s):  
Kazuhiro NOMURA ◽  
Hirotaka IMAI ◽  
Tomoko KOUMURA ◽  
Toshihide KOBAYASHI ◽  
Yasuhito NAKAGAWA
Keyword(s):  
Cytochrome C ◽  
Glutathione Peroxidase ◽  
Acridine Orange ◽  
Phospholipid Hydroperoxide Glutathione Peroxidase ◽  
Primary Event ◽  
Phospholipid Hydroperoxide ◽  
Cyt C ◽  
Mitochondrial Lipid ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis

Cytochrome c (cyt. c) is a proapoptotic factor that binds preferentially to cardiolipin (CL), a mitochondrial lipid, but not to cardiolipin hydroperoxide (CL-OOH). Cyt. c that had bound to CL liposomes was liberated on peroxidation of the liposomes by a radical. The generation of CL-OOH in mitochondria occurred before the release of cyt. c in rat basophile leukaemia (RBL)2H3 cells that had been induced to undergo apoptosis by exposure to hypoglycaemia with 2-deoxyglucose (2DG). The amount of cyt. c bound to CL prepared from the mitochondria of 2DG-treated cells was lower than that of untreated cells. The release of cyt. c was completely suppressed when the production of CL-OOH in mitochondria was inhibited by the overexpression of mitochondrial phospholipid hydroperoxide glutathione peroxidase (PHGPx). The fluorescence from CL-labelling dye (10-N-nonyl Acridine Orange) decreased on the induction of apoptosis by 2DG. However, no decrease in fluorescence was observed in PHGPx-overexpressing cells. Cyt. c was released from mitochondria that had been isolated from control cells on peroxidation by t-butylhydroperoxide, but no similar liberation of cyt. c from mitochondria isolated from mitochondrial PHGPx-overexpressing cells was observed. These findings suggest that the generation of CL-OOH in mitochondria might be a primary event that triggers the release of cyt. c from mitochondria in the apoptotic process in which mitochondrial PHGPx participates as an anti-apoptotic factor by preventing the formation of CL-OOH.

scholarly journals Antrocin Sensitizes Prostate Cancer Cells to Radiotherapy through Inhibiting PI3K/AKT and MAPK Signaling Pathways

Cancers ◽  
2018 ◽  
Vol 11 (1) ◽  
pp. 34 ◽  
Author(s):  
Yu-An Chen ◽  
David T. W. Tzeng ◽  
Yi-Ping Huang ◽  
Chun-Jung Lin ◽  
U-Ging Lo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathways ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Mapk Signaling ◽  
Downstream Signaling ◽  
Cancer Types ◽  
Induced Apoptosis ◽  
Mapk Signaling Pathways

Radiotherapy is one of the most common treatment options for local or regional advanced prostate cancer (PCa). Importantly, PCa is prone to radioresistance and often develops into malignancies after long-term radiotherapy. Antrocin, a sesquiterpene lactone isolated from Antrodia cinnamomea, possesses pharmacological efficacy against various cancer types; however, its therapeutic potential requires comprehensive exploration, particularly in radioresistant PCa cells. In this study, we emphasized the effects of antrocin on radioresistant PCa cells and addressed the molecular mechanism underlying the radiosensitization induced by antrocin. Our results showed that a combination treatment with antrocin and ionizing radiation (IR) synergistically inhibited cell proliferation and induced apoptosis in radioresistant PCa cells. We further demonstrated that antrocin downregulated PI3K/AKT and MAPK signaling pathways as well as suppressed type 1 insulin-like growth factor 1 receptor (IGF-1R)-mediated induction of β-catenin to regulate cell cycle and apoptosis. Using xenograft mouse models, we showed that antrocin effectively enhanced radiotherapy in PCa. Our study demonstrates that antrocin sensitizes PCa to radiation through constitutive suppression of IGF-1R downstream signaling, revealing that it can be developed as a potent therapeutic agent to overcome radioresistant PCa.

scholarly journals How to Turn an Electron Transfer Protein into a Redox Enzyme for Biosensing

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4950
Author(s):  
Antonio Ranieri ◽  
Marco Borsari ◽  
Stefano Casalini ◽  
Giulia Di Rocco ◽  
Marco Sola ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Cytochrome C ◽  
Physiological Role ◽  
Self Assembled Monolayers ◽  
Redox Enzyme ◽  
Transfer Protein ◽  
Electron Transfer Protein ◽  
Transport Chain ◽  
Assembled Monolayers ◽  
Biological Electron Transfer

Cytochrome c is a small globular protein whose main physiological role is to shuttle electrons within the mitochondrial electron transport chain. This protein has been widely investigated, especially as a paradigmatic system for understanding the fundamental aspects of biological electron transfer and protein folding. Nevertheless, cytochrome c can also be endowed with a non-native catalytic activity and be immobilized on an electrode surface for the development of third generation biosensors. Here, an overview is offered of the most significant examples of such a functional transformation, carried out by either point mutation(s) or controlled unfolding. The latter can be induced chemically or upon protein immobilization on hydrophobic self-assembled monolayers. We critically discuss the potential held by these systems as core constituents of amperometric biosensors, along with the issues that need to be addressed to optimize their applicability and response.

Induction of Apoptosis by Nano‐Synthesized Complexes of H2L and its Cu(II) Complex in Human Hepatocellular Carcinoma Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Thoria Diab ◽  
Tarek M. Mohamed ◽  
Alaa Hamed ◽  
Mohamed Gaber
Keyword(s):  
Cell Cycle ◽  
Metal Complexes ◽  
Hepg2 Cells ◽  
Therapeutic Potential ◽  
Free Ligand ◽  
Organometallic Complexes ◽  
Phase Cell ◽  
Sod Activity ◽  
Induced Apoptosis

Background: Chemotherapy is currently the most utilized treatment for cancer. Therapeutic potential of metal complexes in cancer therapy has attracted a lot of interest. The mechanisms of action of most organometallic complexes are poorly understood. Objective: This study was designed to explore the mechanisms governing the anti-proliferative effect of the free ligand N1,N6‐bis((2‐hydroxynaphthalin‐1‐yl)methinyl)) adipohydrazone (H2L) and its complexes of Mn(II), Co(II), Ni(II) and Cu(II). Methods: Cells were exposed to H2L or its metal complexes where cell viability determined by MTT assay. Cell cycle was analysed by flow cytometry. In addition, qRT-PCR was used to monitor the expression of Bax and Bcl-2. Moreover, molecular docking was carried out to find the potentiality of Cu(II) complex as an inhibitor of Adenosine Deaminase (ADA). ADA, Superoxide Dismutase (SOD) and reduced Glutathione (GSH) levels were measured in the most affected cancer cell line. Results: The obtained results demonstrated that H2L and its Cu(II) complex exhibited a strong cytotoxic activity compared to other complexes against HepG2 cells (IC50 = 4.14±0.036μM/ml and 3.2±0.02μM/ml), respectively. Both H2L and its Cu(II) complex induced G2/M phase cell cycle arrest in HepG2 cells. Additionally, they induced apoptosis in HepG2 cells via upregulation of Bax and downregulation of Bcl-2. Interestingly, the activity of ADA was decreased by 2.8 fold in HepG2 cells treated with Cu(II) complex compared to untreated cells. An increase of SOD activity and GSH level in HepG2 cells compared to control was observed. Conclusion: The results concluded that Cu(II) complex of H2L induced apoptosis in HepG2 cells. Further studies are needed to confirm its anti-cancer effect in vivo.

scholarly journals Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS-Mutant Melanoma Cell Lines

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2012
Author(s):  
Kathryn M. Appleton ◽  
Charuta C. Palsuledesai ◽  
Sean A. Misek ◽  
Maja Blake ◽  
Joseph Zagorski ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Therapeutic Potential ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Intrinsic Resistance ◽  
Primary Resistance ◽  
Induced Apoptosis ◽  
Melanoma Cell Lines

The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% BRAFV600 mutations and ≈30% NRAS mutations). While drugs targeting the MAPK pathway have yielded success in BRAFV600 mutant melanoma patients, such therapies have been ineffective in patients with NRAS mutant melanomas in part due to their cytostatic effects and primary resistance. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells, which are highly resistant to trametinib. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

scholarly journals Analysis of redox regulation of cytochrome c-induced apoptosis in a cell-free system

1999 ◽  
Vol 6 (7) ◽  
pp. 683-688 ◽  
Author(s):  
Zhaohui Pan ◽  
David W Voehringer ◽  
Raymond E Meyn
Keyword(s):  
Cytochrome C ◽  
Redox Regulation ◽  
Free System ◽  
Cell Free System ◽  
A Cell ◽  
Induced Apoptosis

Prevention of TNF-α-induced apoptosis in polyamine-depleted IEC-6 cells is mediated through the activation of ERK1/2

2004 ◽  
Vol 286 (3) ◽  
pp. G479-G490 ◽  
Author(s):  
Sujoy Bhattacharya ◽  
Ramesh M. Ray ◽  
Leonard R. Johnson
Keyword(s):  
Epithelial Cells ◽  
Cytochrome C ◽  
Critical Role ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Cytochrome C Release ◽  
Erk Phosphorylation ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
Jnk Activation

It has been documented that polyamines play a critical role in the regulation of apoptosis in intestinal epithelial cells. We have recently reported that protection from TNF-α/cycloheximide (CHX)-induced apoptosis in epithelial cells depleted of polyamines is mediated through the inactivation of a proapoptotic mediator, JNK. In this study, we addressed the involvement of the MAPK pathway in the regulation of apoptosis after polyamine depletion of IEC-6 cells. Polyamine depletion by α-difluromethylornithine (DFMO) resulted in the sustained activation of ERK in response to TNF-α/CHX treatment. Pretreatment of polyamine-depleted IEC-6 cells with a cell membrane-permeable MEK1/2 inhibitor, U-0126, significantly inhibited TNF-α/CHX-induced ERK phosphorylation and significantly increased DNA fragmentation, JNK activity, and caspase-3 activity in response to TNF-α/CHX. Moreover, the dose dependency of U-0126-mediated inhibition of TNF-α/ CHX-induced ERK phosphorylation correlated with the reversal of the antiapoptotic effect of DFMO. IEC-6 cells expressing constitutively active MEK1 had decreased TNF-α/CHX-induced JNK phosphorylation and were significantly protected from apoptosis. Conversely, a dominant-negative MEK1 resulted in high basal activation of JNK, cytochrome c release, and spontaneous apoptosis. Polyamine depletion of the dominant-negative MEK1 cells did not prevent JNK activation or cytochrome c release and failed to confer protection from both TNF-α/CHX and camptothecin-induced apoptosis. Finally, expression of a dominant-negative mutant of JNK significantly protected IEC-6 cells from TNF-α/CHX-induced apoptosis. These data indicate that polyamine depletion results in the activation of ERK, which inhibits JNK activation and protects cells from apoptosis.

Oligomycin and antimycin A prevent nitric oxide–induced apoptosis by blocking cytochrome C leakage

2004 ◽  
Vol 143 (3) ◽  
pp. 143-151 ◽  
Author(s):  
Naohiro Dairaku ◽  
Katsuaki Kato ◽  
Kennichi Honda ◽  
Tomoyuki Koike ◽  
Katsunori Iijima ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cytochrome C ◽  
Antimycin A ◽  
Induced Apoptosis

scholarly journals RIPK1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved ER stress conditions

2014 ◽  
Vol 5 (12) ◽  
pp. e1555-e1555 ◽  
Author(s):  
Y Estornes ◽  
M A Aguileta ◽  
C Dubuisson ◽  
J De Keyser ◽  
V Goossens ◽  
...  
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Death Receptor ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Life And Death ◽  
Unfolded Protein ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and results in the activation of the unfolded protein response (UPR), which aims at restoring ER homeostasis. However, when the stress is too severe the UPR switches from being a pro-survival response to a pro-death one, and the molecular mechanisms underlying ER stress-mediated death have remained incompletely understood. In this study, we identified receptor interacting protein kinase 1 (RIPK1)—a kinase at the crossroad between life and death downstream of various receptors—as a new regulator of ER stress-induced death. We found that Ripk1-deficient MEFs are protected from apoptosis induced by ER stressors, which is reflected by reduced caspase activation and PARP processing. Interestingly, the pro-apoptotic role of Ripk1 is independent of its kinase activity, is not regulated by its cIAP1/2-mediated ubiquitylation, and does not rely on the direct regulation of JNK or CHOP, two reportedly main players in ER stress-induced death. Instead, we found that ER stress-induced apoptosis in these cells relies on death receptor-independent activation of caspase-8, and identified Ripk1 upstream of caspase-8. However, in contrast to RIPK1-dependent apoptosis downstream of TNFR1, we did not find Ripk1 associated with caspase-8 in a death-inducing complex upon unresolved ER stress. Our data rather suggest that RIPK1 indirectly regulates caspase-8 activation, in part via interaction with the ER stress sensor inositol-requiring protein 1 (IRE1).

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