Targeting mutant p53 for cancer therapy: direct and indirect strategies

Journal of Hematology & Oncology, Journal Year: 2021, Volume and Issue: 14(1)

Published: Sept. 28, 2021

TP53 is a critical tumor-suppressor gene that mutated in more than half of all human cancers. Mutations not only impair its antitumor activity, but also confer mutant p53 protein oncogenic properties. The p53-targeted therapy approach began with the identification compounds capable restoring/reactivating wild-type functions or eliminating p53. Treatments directly target are extremely structure and drug-species-dependent. Due to mutation p53, multiple survival pathways normally maintained by disrupted, necessitating activation compensatory genes promote cancer cell survival. Additionally, because contribute proliferation metastasis, targeting signaling altered appears be an attractive strategy. Synthetic lethality implies while disruption either alone permissible among two synthetic lethal interactions, complete both results death. Thus, rather exploiting may provide additional therapeutic benefits. research progress on noncoding RNAs has made it clear disrupting RNA networks favorable effect, supporting hypothesis have potential effects cancers mutations. purpose this review discuss treatments for focus restoring functions, interactions possibility acting as targets will discussed.

Language: Английский

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The Effect of Novel 7-methyl-5-phenyl-pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine Sulfonamide Derivatives on Apoptosis and Autophagy in DLD-1 and HT-29 Colon Cancer Cells

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(15), P. 5221 - 5221

Published: July 23, 2020

The discovery of cytotoxic drugs is focused on designing a compound structure that directly affects cancer cells without an impact normal cells. mechanism anticancer activity mainly related with activation apoptosis. However, recent scientific reports show autophagy also plays crucial role in cell progression. Thus, the objective this study was to synthesize 7-methyl-5-phenyl-pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine utilizing nucleophilic substitution reaction at position N1. biological tested compounds assessed DLD-1 and HT-29 lines. induction apoptosis confirmed by Annexin V binding assay acridine orange/ethidium bromide staining. loss mitochondrial membrane potential caspase-8 estimated using cytometer flow analysis. concentration p53, LC3A, LC3B beclin-1 measured ELISA technique. Our revealed derivatives initiation occur intrinsic pathway decrease extrinsic increase caspase-8. Moreover, beclin-1, were observed two lines after treatment novel compounds. This showed might be strategy colon treatment.

Language: Английский

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Role of tumor and host autophagy in cancer metabolism

Genes & Development, Journal Year: 2019, Volume and Issue: 33(11-12), P. 610 - 619

Published: June 1, 2019

Macroautophagy (referred to here as autophagy) degrades and recycles cytoplasmic constituents sustain cellular mammalian metabolism survival during starvation. Deregulation of autophagy is involved in numerous diseases, such cancer. Cancers up-regulate depend on it for survival, growth, malignancy a tumor cell-autonomous fashion. Recently, has become apparent that host tissues well the cells themselves contribute growth. Understanding how regulates growth revealed new essential nutrients, where they come from, are supplied used, which can now be targeted cancer therapy.

Language: Английский

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Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Dec. 18, 2023

Metastatic dissemination of solid tumors, a leading cause cancer-related mortality, underscores the urgent need for enhanced insights into molecular and cellular mechanisms underlying metastasis, chemoresistance, mechanistic backgrounds individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is mitogen-activated protein kinase (MAPK) pathway, encompassing RAS-RAF-MAPK (MEK)-extracellular signal-related (ERK) pathway. RAF primary mediator MAPK responsible sequential activation downstream targets, such as MEK transcription factor ERK, which control numerous physiological processes, including organism development, cell cycle control, proliferation differentiation, survival, death. Defects in this associated with diseases cancer. (RAFi) combined blockers represent an FDA-approved therapeutic strategy RAF-mutant cancers, melanoma, non-small lung carcinoma, thyroid However, development therapy resistance cancer cells remains important barrier. Autophagy, intracellular lysosome-dependent catabolic recycling process, plays critical role RAFi Thus, targeting autophagy could be novel treatment strategies cancers. In review, we delve deeper surrounding tumorigenesis RAFi-resistance. Furthermore, explore discuss ongoing next-generation profiles. Additionally, review sheds light on functional interplay between RAF-targeted therapies

Language: Английский

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Autophagy and mitophagy in cancer metabolic remodelling

Seminars in Cell and Developmental Biology, Journal Year: 2019, Volume and Issue: 98, P. 129 - 138

Published: June 14, 2019

Language: Английский

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Curcumin induces ferroptosis in non‐small‐cell lung cancer via activating autophagy

Thoracic Cancer, Journal Year: 2021, Volume and Issue: 12(8), P. 1219 - 1230

Published: March 3, 2021

Abstract Background Emerging studies showed curcumin can inhibit glioblastoma and breast cancer cells via regulating ferroptosis. However, the role of ferroptosis in inhibitory effect on non‐small‐cell lung (NSCLC) remains unclear. Methods Cell counting kit‐8 (CCK‐8) assay was used to measure viability A549 H1299 under different conditions. proliferation examined by Ki67 immunofluorescence. The morphological changes tumor tissues were observed optical microscope hematoxylin eosin (H&E) staining. Intracellular reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), iron contents determined corresponding kit. related protein expression levels detected western blot immunohistochemistry. Transmission electron observe ultrastructure cells. Results Curcumin inhibited growth cell proliferation, but promoted death. Characteristic group, including overload, GSH depletion lipid peroxidation. Meanwhile, level ACSL4 higher SLC7A11 GPX4 lower group than that control group. Incubation inhibitors ferrostatin‐1 (Fer‐1) or knockdown iron‐responsive element‐binding 2 (IREB2) notably weakened curcumin‐induced anti‐tumor Further investigation suggested induced mitochondrial membrane rupture cristae decrease, increased autolysosome, Beclin1 LC3, decreased P62. Curcumin‐induced autophagy subsequent both alleviated with inhibitor chloroquine (CQ) siBeclin1. Conclusion activating NSCLC, which enhanced therapeutic NSCLC.

Language: Английский

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Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma

World Journal of Gastroenterology, Journal Year: 2018, Volume and Issue: 24(41), P. 4643 - 4651

Published: Nov. 6, 2018

Autophagy is a "self-degradative" process and involved in the maintenance of cellular homeostasis control components by facilitating clearance or turnover long-lived misfolded proteins, protein aggregates, damaged organelles. plays dual role cancer, including tumor progression promotion, suggesting that autophagy acts as double-edged sword cancer cells. Liver one greatest leading causes death worldwide due to its high recurrence rate poor prognosis. Especially China, liver has become most common cancers infection hepatitis virus. In primary hepatocellular carcinoma (HCC) type. Considering perniciousness complexity HCC, it essential elucidate function HCC. this review, we summarize physiological analyze tumorigenesis metastasis, discuss therapeutic strategies targeting mechanisms drug-resistance provide potential methods circumvent resistance combined anticancer for HCC patients.

Language: Английский

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<p>The Anti-Cancer Mechanisms of Berberine: A Review</p>

Cancer Management and Research, Journal Year: 2020, Volume and Issue: Volume 12, P. 695 - 702

Published: Jan. 1, 2020

Abstract: Berberine (BBR) has been extensively studied in vivo and vitro experiments. BBR inhibits cell proliferation by regulating cycle autophagy, promoting apoptosis. also invasion metastasis suppressing EMT down-regulating the expression of metastasis-related proteins signaling pathways. In addition, interacting with microRNAs telomerase activity. exerts its anti-inflammation antioxidant properties, regulates tumor microenvironment. This review emphasized that as a potential agent, an effective immunomodulator, is expected to be widely used clinic for cancer therapy. Keywords: berberine, anti-tumor, traditional Chinese medicine,

Language: Английский

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Metformin induces cell cycle arrest, apoptosis and autophagy through ROS/JNK signaling pathway in human osteosarcoma

International Journal of Biological Sciences, Journal Year: 2019, Volume and Issue: 16(1), P. 74 - 84

Published: Dec. 6, 2019

Metformin, an ancient drug commonly used for treating type II diabetes, has been associated to anti-cancer capacity in a variety of developing cancers, though the mechanism remains elusive. Here, we aimed examine inhibitory effect metformin osteosarcoma. Herein, demonstrated that treatment blocked proliferation progression by causing accumulation G2/M phase U2OS and 143B cells. Furthermore, triggered programmed cell death process osteosarcoma lines. Further research indicated induction apoptosis autophagy could remarkably attenuate after ROS scavenger NAC JNK inhibitor SP600125. Additionally, our results showed NAC-suppressed JNK/c-Jun signaling pathway have activated through treatment. Lastly, inhibit growth under safe dose vivo. Thus, propose induce cycle arrest as well death, including autophagy, ROS-dependent cascade human This metformin-induced provides further insights into its antitumor potential molecular illuminates cancer targets

Language: Английский

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Endoplasmic Reticulum Stress and Unfolded Protein Response in Breast Cancer: The Balance between Apoptosis and Autophagy and Its Role in Drug Resistance

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(4), P. 857 - 857

Published: Feb. 16, 2019

The unfolded protein response (UPR) is a stress activated by the accumulation of or misfolded proteins in lumen endoplasmic reticulum (ER) and its uncontrolled activation mechanistically responsible for several human pathologies, including metabolic, neurodegenerative, inflammatory diseases, cancer. Indeed, ER downstream UPR lead to changes levels activities key regulators cell survival autophagy this physiologically finalized restore metabolic homeostasis with integration pro-death or/and pro-survival signals. By contrast, chronic cancer cells widely considered mechanism tumor progression. In review, we focus on relationship between stress, apoptosis, breast interplay resistance anticancer therapies aim disclose novel therapeutic scenarios. hypothesis that may provide molecular targets malignancies discussed.

Language: Английский

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