scholarly journals Insights into the Role of Defective Apoptosis in Cancer Pathogenesis and Therapy

2021 ◽  
Author(s):  
Sonia Thapa ◽  
Rafiq A. Rather ◽  
Shashank K. Singh ◽  
Madhulika Bhagat
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Causative Factor ◽  
Specific Cell ◽  
Apoptotic Signaling ◽  
Antiapoptotic Proteins ◽  
Therapeutic Modalities ◽  
Oncogenic Mutations ◽  
Apoptotic Proteins

One form of programmed cell death (PCD) is apoptosis. Defective apoptosis is an indispensable causative factor in the development of cancer that allows cancer cells to survive longer and favors the accumulation of oncogenic mutations. Further, upregulation of antiapoptotic proteins (e.g., Bcl-2, Mcl-1) and loss of pro-apoptotic proteins (e.g., Bid, Bad, Bax, Bak) strongly favors apoptosis evasion. The ability of cancer cells to evade apoptosis is critical for the progression and clonal expansion of malignantly transformed cells. Defective apoptosis imparts proliferative advantage to cancer cells or cells with the potential to become cancerous. The mechanisms employed by cancer cells to evade apoptosis can be used in the strategic design of therapeutic regimens aimed at exploiting apoptotic signaling networks to ensure tumor-specific cell death. Therefore, to ensure tumor-specific cell death, we may need to exploit the expression and/or function of different components of apoptotic signaling that are critical for maintaining cell survival and are regulated differently in tumor cells than normal cells. Both inhibitors of anti-apoptotic proteins and activators of pro-apoptotic proteins can be used for cancer therapy. In this chapter, we attempted to summarize the knowledge about the molecular mechanisms of defective apoptosis that could be translated into the development of novel therapeutic agents and therapeutic modalities for cancer treatment.

scholarly journals Promotion of Cell Death in Cisplatin-Resistant Ovarian Cancer Cells through KDM1B-DCLRE1B Modulation

2019 ◽  
Vol 20 (10) ◽  
pp. 2443 ◽  
Author(s):  
Yeon Kyu Lee ◽  
Jinyeong Lim ◽  
So Young Yoon ◽  
Jong Cheon Joo ◽  
Soo Jung Park ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Ovarian Cancer Cells ◽  
Repair Gene ◽  
Gynecological Malignancy ◽  
Downstream Target ◽  
Dna Repair Gene ◽  
Cisplatin Sensitivity

Ovarian cancer is the gynecological malignancy with the poorest prognosis, in part due to its high incidence of recurrence. Platinum agents are widely used as a first-line treatment against ovarian cancer. Recurrent tumors, however, frequently demonstrate acquired chemo-resistance to platinum agent toxicity. To improve chemo-sensitivity, combination chemotherapy regimens have been investigated. This study examined anti-tumor effects and molecular mechanisms of cytotoxicity of Oldenlandia diffusa (OD) extracts on ovarian cancer cells, in particular, cells resistant to cisplatin. Six ovarian cancer cells including A2780 and cisplatin-resistant A2780 (A2780cis) as representative cell models were used. OD was extracted with water (WOD) or 50% methanol (MOD). MOD significantly induced cell death in both cisplatin-sensitive cells and cisplatin-resistant cells. The combination treatment of MOD with cisplatin reduced viability in A2780cis cells more effectively than treatment with cisplatin alone. MOD in A2780cis cells resulted in downregulation of the epigenetic modulator KDM1B and the DNA repair gene DCLRE1B. Transcriptional suppression of KDM1B and DCLRE1B induced cisplatin sensitivity. Knockdown of KDM1B led to downregulation of DCLRE1B expression, suggesting that DCLRE1B was a KDM1B downstream target. Taken together, OD extract effectively promoted cell death in cisplatin-resistant ovarian cancer cells under cisplatin treatment through modulating KDM1B and DCLRE1B.

scholarly journals Cell Death Pathways as Therapeutic Targets in Rhabdomyosarcoma

Sarcoma ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Simone Fulda
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Aberrant Expression ◽  
Antiapoptotic Proteins ◽  
Cell Death Pathways ◽  
Rational Development ◽  
Current Therapies ◽  
Key Issues ◽  
Cytotoxic Therapies

Resistance of rhabdomyosarcoma to current therapies remains one of the key issues in pediatric oncology. Since the success of most cytotoxic therapies in the treatment of cancer, for example, chemotherapy, depends on intact signaling pathways that mediate programmed cell death (apoptosis), defects in apoptosis programs in cancer cells may result in resistance. Evasion of apoptosis in rhabdomyosarcoma may be caused by defects in the expression or function of critical mediators of apoptosis or in aberrant expression of antiapoptotic proteins. Therefore, the identification of the molecular mechanisms that confer primary or acquired resistance to apoptosis in rhabdomyosarcoma presents a critical step for the rational development of molecular targeted drugs. This approach will likely open novel perspectives for the treatment of rhabdomyosarcoma.

scholarly journals Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin

2016 ◽  
Author(s):  
Xiao-Dong Xu ◽  
Yan Zhao ◽  
Min Zhang ◽  
Rui-Zhi He ◽  
Xiu-Hui Shi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Combined Treatment ◽  
Protective Role ◽  
Pancreatic Cancer Cells ◽  
Effective Therapeutic Strategy ◽  
Cancer Experience

Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer.

scholarly journals A Priori Activation of Apoptosis Pathways of Tumor (AAAPT) Technology: Development of Targeted Apoptosis Initiators for Cancer Treatment

2019 ◽  
Author(s):  
Raghu Pandurangi ◽  
Marco Tomasetti ◽  
Thillai Verapazham Sekar ◽  
Ramasamy Paulmurugan ◽  
Cynthia Ma ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Technology Development ◽  
Tumor Regression ◽  
A Priori ◽  
Specific Cell ◽  
Cell Death Pathways ◽  
Survival Pathways ◽  
Apoptosis Pathways

AbstractCancer cells develop tactics to circumvent the interventions by desensitizing themselves to interventions. The principle routes of desensitization include a) activation of survival pathways (e.g. NF-kB, PARP) and b) downregulation of cell death pathways (e.g. CD95/CD95L). As a result, it requires high therapeutic dose to achieve tumor regression which, in turn damages normal cells through the collateral damaging effects. Methods are needed to sensitize the low and non-responsive resistant tumor cells including cancer stem cells (CSCs) in order to evoke a better response from the current treatments. Current treatments including chemotherapy can induce cell death only in bulk cancer cells sparing CSCs and cancer resistant cells (CRCs) which are shown to be responsible for high recurrence of disease and low patient survival. Here, we report several novel tumor targeted sensitizers derived from the natural Vitamin E analogue (AMP-001-003). The drug design is based on a novel concept “A priori activation of apoptosis pathways of tumor technology (AAAPT) which is designed to activate specific cell death pathways and inhibit survival pathways simultaneously. Our results indicate that AMP-001-003 sensitize various types of cancer cells including MDA-MB-231 (triple negative breast cancer), PC3 (prostate cancer) and A543 (ling cancer) cells resulting in reducing the IC-50 of doxorubicin in vitro. At higher dose, AMP-001 acts as an anti-tumor agent on its own. The synergy between AMP-001 and doxorubicin could pave a new pathway to use AMP-001 as a neoadjuvant to chemotherapy to achieve a better efficacy and reduced off-target toxicity by the current treatments.Summary StatementA Priori Activation of Apoptosis Pathways of Tumor often referred to as “AAAPT” is a novel targeted tumor sensitizing technology which synergizes with chemotherapy to enhance the treatment efficacy.

scholarly journals Silymarin and Cancer: A Dual Strategy in Both in Chemoprevention and Chemosensitivity

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2009 ◽  
Author(s):  
Dominique Delmas ◽  
Jianbo Xiao ◽  
Anne Vejux ◽  
Virginie Aires
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Organic Anion ◽  
Chemotherapeutic Agents ◽  
Normal Cells ◽  
Antiapoptotic Proteins ◽  
Cell Death Pathways ◽  
Anion Transporters ◽  
Atp Binding Cassettes

Silymarin extracted from milk thistle consisting of flavonolignan silybin has shown chemopreventive and chemosensitizing activity against various cancers. The present review summarizes the current knowledge on the potential targets of silymarin against various cancers. Silymarin may play on the system of xenobiotics, metabolizing enzymes (phase I and phase II) to protect normal cells against various toxic molecules or to protect against deleterious effects of chemotherapeutic agents on normal cells. Furthermore, silymarin and its main bioactive compounds inhibit organic anion transporters (OAT) and ATP-binding cassettes (ABC) transporters, thus contributing to counteracting potential chemoresistance. Silymarin and its derivatives play a double role, namely, limiting the progression of cancer cells through different phases of the cycle—thus forcing them to evolve towards a process of cell death—and accumulating cancer cells in a phase of the cell cycle—thus making it possible to target a greater number of tumor cells with a specific anticancer agent. Silymarin exerts a chemopreventive effect by inducing intrinsic and extrinsic pathways and reactivating cell death pathways by modulation of the ratio of proapoptotic/antiapoptotic proteins and synergizing with agonists of death domains receptors. In summary, we highlight how silymarin may act as a chemopreventive agent and a chemosensitizer through multiple pathways.

Emerging Therapeutic Targets in Oncologic Photodynamic Therapy

2019 ◽  
Vol 24 (44) ◽  
pp. 5268-5295 ◽  
Author(s):  
Gina Manda ◽  
Mihail E. Hinescu ◽  
Ionela V. Neagoe ◽  
Luis F.V. Ferreira ◽  
Rica Boscencu ◽  
...  
Keyword(s):  
Cell Death ◽  
Photodynamic Therapy ◽  
Singlet Oxygen ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
Molecular Networks ◽  
Systems Medicine ◽  
Therapeutic Tools

Background:Reactive oxygen species sustain tumorigenesis and cancer progression through deregulated redox signalling which also sensitizes cancer cells to therapy. Photodynamic therapy (PDT) is a promising anti-cancer therapy based on a provoked singlet oxygen burst, exhibiting a better toxicological profile than chemo- and radiotherapy. Important gaps in the knowledge on underlining molecular mechanisms impede on its translation towards clinical applications.Aims and Methods:The main objective of this review is to critically analyse the knowledge lately gained on therapeutic targets related to redox and inflammatory networks underlining PDT and its outcome in terms of cell death and resistance to therapy. Emerging therapeutic targets and pharmaceutical tools will be documented based on the identified molecular background of PDT.Results:Cellular responses and molecular networks in cancer cells exposed to the PDT-triggered singlet oxygen burst and the associated stresses are analysed using a systems medicine approach, addressing both cell death and repair mechanisms. In the context of immunogenic cell death, therapeutic tools for boosting anti-tumor immunity will be outlined. Finally, the transcription factor NRF2, which is a major coordinator of cytoprotective responses, is presented as a promising pharmacologic target for developing co-therapies designed to increase PDT efficacy.Conclusion:There is an urgent need to perform in-depth molecular investigations in the field of PDT and to correlate them with clinical data through a systems medicine approach for highlighting the complex biological signature of PDT. This will definitely guide translation of PDT to clinic and the development of new therapeutic strategies aimed at improving PDT.

scholarly journals Molecular Mechanisms by Which a Fucus vesiculosus Extract Mediates Cell Cycle Inhibition and Cell Death in Pancreatic Cancer Cells

Marine Drugs ◽  
2015 ◽  
Vol 13 (7) ◽  
pp. 4470-4491 ◽  
Author(s):  
Ulf Geisen ◽  
Marion Zenthoefer ◽  
Matthias Peipp ◽  
Jannik Kerber ◽  
Johannes Plenge ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Fucus Vesiculosus ◽  
Pancreatic Cancer Cells ◽  
Cell Cycle Inhibition

scholarly journals Cinnamaldehyde induces autophagy-mediated cell death through ER stress and epigenetic modification in gastric cancer cells

2021 ◽  
Author(s):  
Tae Woo Kim
Keyword(s):  
Gastric Cancer ◽  
Cell Death ◽  
Er Stress ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Epigenetic Modification ◽  
Autophagic Cell Death ◽  
Beclin 1 ◽  
Gastric Cancer Cells ◽  
Autophagy Inhibition

AbstractPrevious reports suggested that cinnamaldehyde (CA), the bioactive ingredient in Cinnamomum cassia, can suppress tumor growth, migratory, and invasive abilities. However, the role and molecular mechanisms of CA in GC are not completely understood. In the present study, we found that CA-induced ER stress and cell death via the PERK–CHOP axis and Ca2+ release in GC cells. Inhibition of ER stress using specific–siRNA blocked CA-induced cell death. Interestingly, CA treatment resulted in autophagic cell death by inducing Beclin-1, ATG5, and LC3B expression and by inhibiting p62 expression whereas autophagy inhibition suppressed CA-induced cell death. We showed that CA induces the inhibition of G9a and the activation of LC3B. Moreover, CA inhibited G9a binding on Beclin-1 and LC3B promoter. Overall, these results suggested that CA regulates the PERK–CHOP signaling, and G9a inhibition activates autophagic cell death via ER stress in GC cells.

Sign in / Sign up

Export Citation Format

Share Document