Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells.

Mutations in the tumor suppressor TP53 cause cancer and impart poor chemotherapeutic responses, reportedly through loss-of-function, dominant-negative effects and gain-of-function (GOF) activities. The relative contributions of these attributes is unknown. We found that removal of 12 different TP53 mutants with reported GOFs by CRISPR/Cas9 did not impact proliferation and response to chemotherapeutics of 15 human cancer cell lines and colon cancer-derived organoids in culture. Moreover, removal of mutant TP53/TRP53 did not impair growth or metastasis of human cancers in immune-deficient mice or growth of murine cancers in immune-competent mice. DepMap mining revealed that removal of 158 different TP53 mutants had no impact on the growth of 391 human cancer cell lines. In contrast, CRISPR-mediated restoration of wild-type TP53 extinguished the growth of human cancer cells in vitro. These findings demonstrate that LOF but not GOF effects of mutant TP53/TRP53 are critical to sustain expansion of many tumor types. SIGNIFICANCE: This study provides evidence that removal of mutant TP53, thereby deleting its reported GOF activities, does not impact the survival, proliferation, metastasis, or chemotherapy responses of cancer cells. Thus, approaches that abrogate expression of mutant TP53 or target its reported GOF activities are unlikely to exert therapeutic impact in cancer. See related commentary by Lane, p. 211 . This article is featured in Selected Articles from This Issue, p. 201.

Genome-wide CRISPR screening identifies a role for ARRDC3 in TRP53-mediated responses.

Whole-genome screens using CRISPR technologies are powerful tools to identify novel tumour suppressors as well as factors that impact responses of malignant cells to anti-cancer agents. Applying this methodology to lymphoma cells, we conducted a genome-wide screen to identify novel inhibitors of tumour expansion that are induced by the tumour suppressor TRP53. We discovered that the absence of Arrestin domain containing 3 (ARRDC3) increases the survival and long-term competitiveness of MYC-driven lymphoma cells when treated with anti-cancer agents that activate TRP53. Deleting Arrdc3 in mice caused perinatal lethality due to various developmental abnormalities, including cardiac defects. Notably, the absence of ARRDC3 markedly accelerated MYC-driven lymphoma development. Thus, ARRDC3 is a new mediator of TRP53-mediated suppression of tumour expansion, and this discovery may open new avenues to harness this process for cancer therapy.

BH3 mimetics and TKI combined therapy for Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) was considered for a long time one of the most hostile leukemia that was incurable for most of the patients, predominantly due to the extreme resistance to chemotherapy. Part of the resistance to cell death (apoptosis) is the result of increased levels of anti-apoptotic and decreased levels of pro-apoptotic member of the BCL-2 family induced by the BCR-ABL1 oncoprotein. BCR-ABL1 is a constitutively active tyrosine kinase responsible for initiating multiple and oncogenic signaling pathways. With the development of specific BCR-ABL1 tyrosine kinase inhibitors (TKIs) CML became a much more tractable disease. Nevertheless, TKIs do not cure CML patients and a substantial number of them develop intolerance or become resistant to the treatment. Therefore, novel anti-cancer strategies must be developed to treat CML patients independently or in combination with TKIs. Here, we will discuss the mechanisms of BCR-ABL1-dependent and -independent resistance to TKIs and the use of BH3-mimetics as a potential tool to fight CML.

BCL-2 protein family: attractive targets for cancer therapy.

Acquired resistance to cell death is a hallmark of cancer. The BCL-2 protein family members play important roles in controlling apoptotic cell death. Abnormal over-expression of pro-survival BCL-2 family members or abnormal reduction of pro-apoptotic BCL-2 family proteins, both resulting in the inhibition of apoptosis, are frequently detected in diverse malignancies. The critical role of the pro-survival and pro-apoptotic BCL-2 family proteins in the regulation of apoptosis makes them attractive targets for the development of agents for the treatment of cancer. This review describes the roles of the various pro-survival and pro-apoptotic members of the BCL-2 protein family in normal development and organismal function and how defects in the control of apoptosis promote the development and therapy resistance of cancer. Finally, we discuss the development of inhibitors of pro-survival BCL-2 proteins, termed BH3-mimetic drugs, as novel agents for cancer therapy.

Pharmaceutical effluent: a critical link in the interconnected ecosystem promoting antimicrobial resistance.

Antimicrobial resistance (AMR) is a complex global health issue and will push twenty-four million people into extreme poverty by 2030, risking the sustainable development goals (SDGs) 2, 3, 6, 9, 12, and 17 if not addressed immediately. Humans, animals, and the environment are the reservoirs that contribute and allow AMR to propagate in interconnected ecosystems. The emergence of antibiotic-resistant bacteria and antibiotic-resistant genes in the water environment has become an important environmental health issue. One of the major influencers from environment sector is the pharmaceutical industry which is growing globally to meet the ever-increasing demand of antibiotics, especially in low- and middle-income countries. The pharmaceutical effluent has a mix of large concentrations of antibiotics and antibiotic resistance genes, and these sites act as hotspots for environmental contamination and the spread of AMR. Inadequate treatment of the effluent and its irresponsible disposal leads to unprecedented antibiotic contamination in the environment and their persistent presence in the environment significantly modulates the bacterial genomes' expression that is responsible for increase and spread of AMR. However, not much interventions are suggested in the National Action Plan developed on AMR by many countries. There are no regulations across the globe till date for the level of antibiotic residues in pharmaceutical effluent for the growing pharmaceutical industry. This review put together the work done showing several detrimental effects of the antimicrobial residues in the pharmaceutical effluent which leads to rise in development of AMR. The environment risk approach and need to have indicators to measure environment risk is a way forward for all countries engage in antibiotic manufacturing. Overall, efforts to address the problem are isolated and fragmented. Policymakers, regulators, manufacturers, researchers, civil society, and the community need to collaborate so that antibiotics are produced sustainably and continue to stay effective in treating bacterial infections.

Knowledge and behavior of consumers towards the non-prescription purchase of antibiotics: An insight from a qualitative study from New Delhi, India.

BACKGROUND: In Low-and Middle-Income Countries, including India, consumers often purchase antibiotics over-the-counter (OTC) from retail pharmacies. This practice leads to the inappropriate use of antibiotics in the community which is an important driver for the development of antimicrobial resistance. A better understanding of consumers' views towards this grave public health concern is critical to developing evidence-based intervention programs for awareness among the general population. OBJECTIVE: To explore knowledge, practice and, behavior of consumers towards antibiotics, antibiotic use, antimicrobial resistance, purchasing behavior of consumers for antibiotics, and to gain insight which will help in developing evidence-based policy interventions. METHODS: 72 in-depth consumer interviews were conducted in all 11 districts of the National Capital Territory of Delhi. The qualitative data were analyzed using thematic analysis. RESULTS: Our study found that retail pharmacies were the first point of consultation for common ailments for patients/consumers once home remedies failed; they were largely unaware of the threat of antimicrobial resistance. Consumers' knowledge of antibiotic use and about antimicrobial resistance was low, they used old prescriptions, and bought antibiotics OTC to save time and money. Despite the presence of regulations constituted to regulate the sale of antibiotics by the Government and the implementation of national campaigns, the practice of self-medication and behaviors such as OTC purchase, non-adherence to prescribed antibiotics was prevalent. Consumers perceive that antibiotics provide quick relief and accelerate the curing process and retail pharmacy shops try to protect their retail business interests by honoring old prescriptions and self-medication for antibiotics. CONCLUSIONS: The lack of awareness and insufficient knowledge about what antibiotics are and issues such as antimicrobial resistance or antibiotic resistance resulted in misuse of antibiotics by consumers. Limited access to public healthcare and affordability of private healthcare are factors that contribute towards the self-medication/OTC purchase of antibiotics. The regular misuse of antibiotics through irrational use reinforces the need for strong enactment of strategies like continuous community awareness campaigns. Mitigation efforts should focus upon educating consumers continuously and sustainably for the understanding of antibiotic misuse, antimicrobial resistance, and promote better compliance with regulations.

Knowledge and behavior of consumers towards the non-prescription purchase of antibiotics: an insight from a qualitative study from New Delhi, India

BACKGROUND: In Low-and Middle-Income Countries, including India, consumers often purchase antibiotics over-the-counter (OTC) from retail pharmacies. This practice leads to the inappropriate use of antibiotics in the community which is an important driver for the development of antimicrobial resistance. A better understanding of consumers' views towards this grave public health concern is critical to developing evidence-based intervention programs for awareness among the general population. OBJECTIVE: To explore knowledge, practice and, behavior of consumers towards antibiotics, antibiotic use, antimicrobial resistance, purchasing behavior of consumers for antibiotics, and to gain insight which will help in developing evidence-based policy interventions. METHODS: 72 in-depth consumer interviews were conducted in all 11 districts of the National Capital Territory of Delhi. The qualitative data were analyzed using thematic analysis. RESULTS: Our study found that retail pharmacies were the first point of consultation for common ailments for patients/consumers once home remedies failed; they were largely unaware of the threat of antimicrobial resistance. Consumers' knowledge of antibiotic use and about antimicrobial resistance was low, they used old prescriptions, and bought antibiotics OTC to save time and money. Despite the presence of regulations constituted to regulate the sale of antibiotics by the Government and the implementation of national campaigns, the practice of self-medication and behaviors such as OTC purchase, non-adherence to prescribed antibiotics was prevalent. Consumers perceive that antibiotics provide quick relief and accelerate the curing process and retail pharmacy shops try to protect their retail business interests by honoring old prescriptions and self-medication for antibiotics. CONCLUSIONS: The lack of awareness and insufficient knowledge about what antibiotics are and issues such as antimicrobial resistance or antibiotic resistance resulted in misuse of antibiotics by consumers. Limited access to public healthcare and affordability of private healthcare are factors that contribute towards the self-medication/OTC purchase of antibiotics. The regular misuse of antibiotics through irrational use reinforces the need for strong enactment of strategies like continuous community awareness campaigns. Mitigation efforts should focus upon educating consumers continuously and sustainably for the understanding of antibiotic misuse, antimicrobial resistance, and promote better compliance with regulations

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