scholarly journals Targeting Mitochondrial Apoptosis to Overcome Treatment Resistance in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 574 ◽  
Author(s):  
Natalie Yan Li Ngoi ◽  
Clarice Choong ◽  
Joanne Lee ◽  
Gregory Bellot ◽  
Andrea LA Wong ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Cell Fate ◽  
Cancer Progression ◽  
Chemotherapy Resistance ◽  
Family Members ◽  
Biological Significance ◽  
Treatment Resistance ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Mitochondrial Apoptosis

Deregulated cellular apoptosis is a hallmark of cancer and chemotherapy resistance. The B-cell lymphoma 2 (BCL-2) protein family members are sentinel molecules that regulate the mitochondrial apoptosis machinery and arbitrate cell fate through a delicate balance between pro- and anti-apoptotic factors. The recognition of the anti-apoptotic BCL2 gene as an oncogenic driver in hematological malignancies has directed attention toward unraveling the biological significance of each of the BCL-2 superfamily members in cancer progression and garnered interest in the targeting of apoptosis in cancer therapy. Accordingly, the approval of venetoclax (ABT-199), a small molecule BCL-2 inhibitor, in patients with chronic lymphocytic leukemia and acute myeloid leukemia has become the proverbial torchbearer for novel candidate drug approaches selectively targeting the BCL-2 superfamily. Despite the inspiring advances in this field, much remains to be learned regarding the optimal therapeutic context for BCL-2 targeting. Functional assays, such as through BH3 profiling, may facilitate prediction of treatment response, development of drug resistance and shed light on rational combinations of BCL-2 inhibitors with other branches of cancer therapy. This review summarizes the pathological roles of the BCL-2 family members in cancer, discusses the current landscape of their targeting in clinical practice, and highlights the potential for future therapeutic inroads in this important area.

Therapeutics targeting Bcl-2 in hematological malignancies

2017 ◽  
Vol 474 (21) ◽  
pp. 3643-3657 ◽  
Author(s):  
Astrid Ruefli-Brasse ◽  
John C. Reed
Keyword(s):  
Cancer Therapy ◽  
B Cell ◽  
Clinical Utility ◽  
Family Members ◽  
B Cell Lymphoma ◽  
Selective Inhibition ◽  
Lymphocytic Leukemia ◽  
Combination Therapies ◽  
Fda Approval ◽  
Selective Targeting

Members of the B-cell lymphoma 2 (BCL-2) gene family are attractive targets for cancer therapy as they play a key role in promoting cell survival, a long-since established hallmark of cancer. Clinical utility for selective inhibition of specific anti-apoptotic Bcl-2 family proteins has recently been realized with the Food and Drug Administration (FDA) approval of venetoclax (formerly ABT-199/GDC-0199) in relapsed chronic lymphocytic leukemia (CLL) with 17p deletion. Despite the impressive monotherapy activity in CLL, such responses have rarely been observed in other B-cell malignancies, and preclinical data suggest that combination therapies will be needed in other indications. Additional selective antagonists of Bcl-2 family members, including Bcl-XL and Mcl-1, are in various stages of preclinical and clinical development and hold the promise of extending clinical utility beyond CLL and overcoming resistance to venetoclax. In addition to direct targeting of Bcl-2 family proteins with BH3 mimetics, combination therapies that aim at down-regulating expression of anti-apoptotic BCL-2 family members or restoring expression of pro-apoptotic BH3 family proteins may provide a means to deepen responses to venetoclax and extend the utility to additional indications. Here, we review recent progress in direct and selective targeting of Bcl-2 family proteins for cancer therapy and the search for rationale combinations.

scholarly journals BCL-2 Proteins in Pathogenesis and Therapy of B-Cell Non-Hodgkin Lymphomas

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 938 ◽  
Author(s):  
Magdalena Klanova ◽  
Pavel Klener
Keyword(s):  
B Cell ◽  
Protein Interactions ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Mitochondrial Apoptosis ◽  
Clinical Testing ◽  
Cell Leukemia ◽  
The Status ◽  
B Cell Leukemia

The ability to inhibit mitochondrial apoptosis is a hallmark of B-cell non-Hodgkin lymphomas (B-NHL). Activation of mitochondrial apoptosis is tightly controlled by members of B-cell leukemia/lymphoma-2 (BCL-2) family proteins via protein-protein interactions. Altering the balance between anti-apoptotic and pro-apoptotic BCL-2 proteins leads to apoptosis evasion and extended survival of malignant cells. The pro-survival BCL-2 proteins: B-cell leukemia/lymphoma-2 (BCL-2/BCL2), myeloid cell leukemia-1 (MCL-1/MCL1) and B-cell lymphoma-extra large (BCL-XL/BCL2L1) are frequently (over)expressed in B-NHL, which plays a crucial role in lymphoma pathogenesis, disease progression, and drug resistance. The efforts to develop inhibitors of anti-apoptotic BCL-2 proteins have been underway for several decades and molecules targeting anti-apoptotic BCL-2 proteins are in various stages of clinical testing. Venetoclax is a highly specific BCL-2 inhibitor, which has been approved by the US Food and Drug Agency (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL) and is in advanced clinical testing in other types of B-NHL. In this review, we summarize the biology of BCL-2 proteins and the mechanisms of how these proteins are deregulated in distinct B-NHL subtypes. We describe the mechanism of action of BH3-mimetics and the status of their clinical development in B-NHL. Finally, we summarize the mechanisms of sensitivity/resistance to venetoclax.

scholarly journals Risk of hematological malignancies in the families of patients treated for nodular lymphocyte-predominant Hodgkin lymphoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Saad Akhtar ◽  
M. Shahzad Rauf ◽  
Amani Al-Kofide ◽  
Mahmoud A. Elshenawy ◽  
Ali Hassan Mushtaq ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Hematological Malignancies ◽  
Cell Lymphoma ◽  
Lymphoblastic Leukemia ◽  
Family Members ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
2Nd Generation ◽  
Non Hodgkin Lymphoma ◽  
Phone Calls

Abstract Background Familial clustering of lymphoid and/or hematological malignancies (FHM) provides an opportunity to study the responsible genes. The data is limited in patients with lymphoid and hematological malignancies. Methods The lymphoma database was used to identify patients seen in our institution from 1998 to 2019 with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). We studied FHM by collecting detailed history of any malignancy in the family (FM). Results Two hundred NLPHL patients were identified. Contacting was not possible in 30 patients due to no response to the phone calls (22) and death [1]. 170/200 patients were interviewed; represented 167 families (3 patients with a family member with NLPHL). These 170 patients provided information about 8225 family members. These 167 families had a total of 329 family members with 334 malignancies (including 167 NLPHL patients and 5 members with 2 malignancies each). Of these 167 patients, 77 (46.1%) had no FM while 90 (53.9%) patients had a positive FM; 162 family members with 167 malignancies. Among these 167 families, 31 families (18.6%) had members with FHM +/− solid cancers. These 31 families had 35 family members (25 males:10 females) with 16 lymphomas: diffuse large B cell lymphoma [2], follicular center cell lymphoma [3], chronic lymphocytic leukemia/small lymphocytic lymphoma [3], non-Hodgkin lymphoma [2], classical HL [2], and NLPHL [4]. Total of 8 leukemia: acute lymphoblastic leukemia [4], acute myeloid leukemia [3], and leukemia - no subtyping [5]. These 35 FHM members are 1st [6], 2nd (16), and 3rd [7] degree relatives of 31 NLPHL patients. There are 4 families with NLPHL in family members; all these 8 NLPHL patients are male and are alive. The median total number of 1st + 2nd +3rd degree members are 81. The decrease in the age of diagnosis from 1st generation to the 2nd generation (anticipation) was noted in 13/17 patients; 2nd generation median age at diagnosis was 29.7 years vs 1st generation age 53 years (developed malignancy 23.3 years earlier). Conclusion FHM is frequent in NLPHL. This study provided us many important insights for planning future studies in terms of interviewing technique, time, and resource allocation and genetic testing.

scholarly journals The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 838 ◽  
Author(s):  
Nele Loret ◽  
Hannelore Denys ◽  
Philippe Tummers ◽  
Geert Berx
Keyword(s):  
Ovarian Cancer ◽  
Cell Fate ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Chemotherapy Resistance ◽  
Therapy Resistance ◽  
Cancer Resistance ◽  
Mesenchymal Transition ◽  
Development Of Resistance ◽  
Cancer Cell Survival

Ovarian cancer is the most lethal of all gynecologic malignancies and the eighth leading cause of cancer-related deaths among women worldwide. The main reasons for this poor prognosis are late diagnosis; when the disease is already in an advanced stage, and the frequent development of resistance to current chemotherapeutic regimens. Growing evidence demonstrates that apart from its role in ovarian cancer progression, epithelial-to-mesenchymal transition (EMT) can promote chemotherapy resistance. In this review, we will highlight the contribution of EMT to the distinct steps of ovarian cancer progression. In addition, we will review the different types of ovarian cancer resistance to therapy with particular attention to EMT-mediated mechanisms such as cell fate transitions, enhancement of cancer cell survival, and upregulation of genes related to drug resistance. Preclinical studies of anti-EMT therapies have yielded promising results. However, before anti-EMT therapies can be effectively implemented in clinical trials, more research is needed to elucidate the mechanisms leading to EMT-induced therapy resistance.

Validation of a Cyclic Algorithm to Proxy Number of Lines of Systemic Cancer Therapy Using Administrative Data

2019 ◽  
pp. 1-10
Author(s):  
Deirdre Weymann ◽  
Sarah Costa ◽  
Dean A. Regier
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cancer Therapy ◽  
Cell Lymphoma ◽  
Pearson Correlation ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Large B Cell Lymphoma ◽  
Out Of Sample ◽  
Cyclic Algorithm ◽  
Large B Cell

PURPOSE Researchers are automating the process for identifying the number of lines of systemic cancer therapy received by patients. To date, algorithm development has involved manual modifications to predefined classification rules. In this study, we propose a supervised learning algorithm for determining the best-performing proxy for number of lines of therapy and validate this approach in four patient groups. MATERIALS AND METHODS We retrospectively analyzed BC Cancer pharmacy records from patients’ cancer diagnosis until end of follow-up (cohort-specific, 2014/2015). We created and validated a cyclic algorithm in patients with advanced cancers of varying histologies, diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. To assess internal and external validity, we used a split-sample approach for all analyses and considered lines of therapy identified through manual review as our criterion standard. We measured agreement using correlation coefficients, mean squared error, nonparametric hypothesis testing, and quantile-quantile plots. RESULTS Cohorts comprised 91 patients with advanced cancers, 121 with chronic lymphocytic leukemia, 440 with follicular lymphoma, and 679 with diffuse large B-cell lymphoma. Number of lines of therapy received and patients’ treatment period length varied substantially across cohorts. Despite these differences, our algorithm successfully identified a best-performing proxy for number of lines of therapy for each cohort, which was moderate to highly correlated with (within-sample: 0.73 ≤ Pearson correlation ≤ 0.84; out-of-sample: 0.52 ≤ Pearson correlation ≤ 0.76) and whose distribution did not significantly differ from the criterion standard within or out of sample ( P > .10). CONCLUSION Supervised learning is an ideal tool for generating a best-performing proxy that recognizes prescription drug patterns and approximates number of lines of therapy. Our cyclic approach can be used in jurisdictions with access to administrative pharmacy data.

scholarly journals Transcription Factors: The Fulcrum Between Cell Development and Carcinogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Zeyaul Islam ◽  
Ameena Mohamed Ali ◽  
Adviti Naik ◽  
Mohamed Eldaw ◽  
Julie Decock ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Cancer Progression ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Tumor Development ◽  
Treatment Resistance ◽  
Cell Development ◽  
Fate Decision ◽  
And Function

Higher eukaryotic development is a complex and tightly regulated process, whereby transcription factors (TFs) play a key role in controlling the gene regulatory networks. Dysregulation of these regulatory networks has also been associated with carcinogenesis. Transcription factors are key enablers of cancer stemness, which support the maintenance and function of cancer stem cells that are believed to act as seeds for cancer initiation, progression and metastasis, and treatment resistance. One key area of research is to understand how these factors interact and collaborate to define cellular fate during embryogenesis as well as during tumor development. This review focuses on understanding the role of TFs in cell development and cancer. The molecular mechanisms of cell fate decision are of key importance in efforts towards developing better protocols for directed differentiation of cells in research and medicine. We also discuss the dysregulation of TFs and their role in cancer progression and metastasis, exploring TF networks as direct or indirect targets for therapeutic intervention, as well as specific TFs’ potential as biomarkers for predicting and monitoring treatment responses.

Acid ceramidase, a double-edged sword in cancer aggression: A minireview

2020 ◽  
Vol 20 ◽  
Author(s):  
Helen Shiphrah Vethakanraj ◽  
Niveditha Chandrasekaran ◽  
Ashok Kumar Sekar
Keyword(s):  
Cell Fate ◽  
Cancer Progression ◽  
Potential Role ◽  
Tumour Progression ◽  
Acid Ceramidase ◽  
The Core ◽  
The Past ◽  
Sphingosine 1 Phosphate ◽  
Key Enzyme

: Acid ceramidase (AC), the key enzyme of the ceramide metabolic pathway hydrolyzes pro-apoptotic ceramide to sphingosine, which by the action of sphingosine-1-kinase is metabolized to mitogenic sphingosine-1-phosphate. The intracellular level of AC determines ceramide/sphingosine-1-phosphate rheostat which in turn decides the cell fate. The upregulated AC expression during cancerous condition acts as a “double-edged sword” by converting pro-apoptotic ceramide to anti-apoptotic sphingosine-1-phosphate, wherein on one end, the level of ceramide is decreased and on the other end, the level of sphingosine-1-phosphate is increased, thus altogether aggravating the cancer progression. In addition, cancer cells with upregulated AC expression exhibited increased cell proliferation, metastasis, chemoresistance, radioresistance and numerous strategies were developed in the past to effectively target the enzyme. Gene silencing and pharmacological inhibition of AC sensitized the resistant cells to chemo/radiotherapy thereby promoting cell death. The core objective of this review is to explore AC mediated tumour progression and the potential role of AC inhibitors in various cancer cell lines/models.

Cancer Fighting SiRNA-RRM2 Loaded Nanorobots

2020 ◽  
Vol 8 (2) ◽  
pp. 79-90
Author(s):  
Arjun Sharma ◽  
Pravir Kumar ◽  
Rashmi K. Ambasta
Keyword(s):  
Cancer Therapy ◽  
Dna Synthesis ◽  
Cancer Progression ◽  
Sirna Delivery ◽  
Predictive Marker ◽  
The Body ◽  
Tumor Site ◽  
Target Delivery ◽  
Target Effect

Background: Silencing of several genes is critical for cancer therapy. These genes may be apoptotic gene, cell proliferation gene, DNA synthesis gene, etc. The two subunits of Ribonucleotide Reductase (RR), RRM1 and RRM2, are critical for DNA synthesis. Hence, targeting the blockage of DNA synthesis at tumor site can be a smart mode of cancer therapy. Specific targeting of blockage of RRM2 is done effectively by SiRNA. The drawbacks of siRNA delivery in the body include the poor uptake by all kinds of cells, questionable stability under physiological condition, non-target effect and ability to trigger the immune response. These obstacles may be overcome by target delivery of siRNA at the tumor site. This review presents a holistic overview regarding the role of RRM2 in controlling cancer progression. The nanoparticles are more effective due to specific characteristics like cell membrane penetration capacity, less toxicity, etc. RRM2 have been found to be elevated in different types of cancer and identified as the prognostic and predictive marker of the disease. Reductase RRM1 and RRM2 regulate the protein and gene expression of E2F, which is critical for protein expression and progression of cell cycle and cancer. The knockdown of RRM2 leads to apoptosis via Bcl2 in cancer. Both Bcl2 and E2F are critical in the progression of cancer, hence a gene that can affect both in regulating DNA replication is essential for cancer therapy. Aim: The aim of the review is to identify the related gene whose silencing may inhibit cancer progression. Conclusion: In this review, we illuminate the critical link between RRM-E2F, RRM-Bcl2, RRM-HDAC for the therapy of cancer. Altogether, this review presents an overview of all types of SiRNA targeted for cancer therapy with special emphasis on RRM2 for controlling the tumor progression.

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