Strategies for manipulating the p53 pathway in the treatment of human cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Hupp TR
PROVIDER: S-EPMC1221427 | biostudies-other | 2000 Nov
REPOSITORIES: biostudies-other
Similar Datasets
Project description:p53 is one of the most well-studied tumor suppressors. It is mutated or deleted in half of all cancers. In the other half carrying wild type p53, the p53 signaling pathway is disrupted by abnormalities of other components in the pathway. Due to its paramount role in tumor suppression, p53 has attracted great interest in drug development as any clinically successful therapeutic agent to target the p53 pathway will save millions of lives. However, designing therapeutics targeting the pathway has been extremely challenging, despite more than forty years of research. This review will summarize past and current efforts of developing p53-based gene therapy and targeted therapies for cancer treatment. In addition, the current efforts of exploiting the immunogenicity of p53 protein for cancer immunotherapy will be reviewed. Challenges and future directions for targeting the p53 pathway will be discussed.
| S-EPMC7969395 | biostudies-literature
Project description:Calcium is one of the most pleiotropic second messengers in all living organisms. However, signalling specificity is encoded via spatio-temporally regulated signatures that act with surgical precision to elicit highly specific cellular responses. How this is brought about remains a big challenge in the plant field, in part due to a lack of specific tools to manipulate/interrogate the plant Ca2+ toolkit. In many cases, researchers resort to tools that were optimized in animal cells. However, the obviously large evolutionary distance between plants and animals implies that there is a good chance observed effects may not be specific to the intended plant target. Here, we provide an overview of pharmacological strategies that are commonly used to activate or inhibit plant Ca2+ signalling. We focus on highlighting modes of action where possible, and warn for potential pitfalls. Together, this review aims at guiding plant researchers through the Ca2+ pharmacology swamp.
| S-EPMC5983822 | biostudies-other
Project description:MiR-34a is a downstream effector of p53 that has been shown to target several molecules associated with cell cycle and cell survival pathways. As alterations in these pathways are frequent in muscle invasive transitional cell carcinoma of the bladder (MI-TCC), for example mutation or loss of p53 and Rb, the goal of this study was to determine whether manipulation of miR-34a expression levels could abrogate the effect of these alterations and sensitize bladder cancer cells to chemotherapy. We demonstrate that transfection of T24, TCCSUP and 5637 with pre-miR-34a followed by cisplatin treatment results in a dramatic reduction in clonogenic potential and induction of senescence compared to treatment with cisplatin alone. Molecular analyses identified Cdk6 and sirtuin (SIRT)-1 as being targeted by miR-34a in MI-TCC cells, however, inhibition of Cdk6 and SIRT-1 was not as effective as pre-miR-34a in mediating chemosensitization. Analysis of 27 preneoadjuvant chemotherapy patient samples revealed many of the patients who subsequently did not respond to treatment (based on surgical resection postchemotherapy and 5-year survival data) express lower levels of miR-34a, however, a statistically significant difference between the responder and nonresponder groups was not observed (p = 0.1174). Analysis of eight sets of pre- and postneoadjuvant chemotherapy patient samples determined miR-34a expression increased postchemotherapy in only two of the eight patients. The combined data indicate that elevation of miR-34a expression levels before chemotherapy would be of benefit to MI-TCC patients, particularly in a setting of low miR-34a expression.
| S-EPMC4568996 | biostudies-literature
Project description:BackgroundDespite the advancement in chemotherapeutic drugs for colon cancer treatment, it is still a life-threatening disease worldwide due to drug resistance. Therefore, an urgently needed to develop novel drugs for colon cancer therapies. AGA is a combination of traditional Chinese medicine Antler's extract (A), Ganoderma lucidum (G), and Antrodia camphorata (A); it contains a lot of biomolecules like polysaccharides, fatty acids, and triterpenoids that are known to exerting anti-oxidative, anti-inflammatory, anti-microbial and anti-tumor activities in oral cancer. In this study, we investigate AGA anti-proliferative, anti-metastatic and apoptotic activity to explore its anti-cancer activity against colon cancer cells and its underlying mechanism.MethodHere, in-vitro studies were performed to determine the antiproliferative activity of AGA through MTT and colony formation assays. Wound healing and transwell migration assay were used to evaluate the metastasis. Flow cytometry and protein expression were used to investigate the involved molecular mechanism by evaluating the cell cycle and apoptosis. The in-vivo anti-cancerous activity of AGA was assessed by xenograft mice model of colon cancer cells.ResultsWe found that AGA significantly inhibited the proliferative capacity and metastasis of colon cancer cells in-vitro. In addition, AGA induced cell cycle arrest in the sub-G1 phase through upregulating p21 and downregulating CDK2, CDK6 in SW620, and CDK4 in SW480 and HT29, respectively. Annexin-v assay indicated that colon cancer cells had entered early and late apoptosis after treatment with AGA. Furthermore, a mechanistic protein expressions study revealed that AGA in p53-dependent and independent regulated the apoptosis of colon cancer by downregulating the p53 protein expression in SW620 and SW480 cells but upregulating in a dose-dependent manner in HT29 cells and increasing the expression of Bax and caspase-9 to inhibit the colon cancer cells. In vivo study, we found that AGA significantly reduced the xenograft tumor growth in NOD/SCID mice with no adverse effect on the kidney and liver.ConclusionCollectively, AGA has the potential to inhibit colon cancer through inhibiting proliferation, migration, and cell cycle kinase by upregulating p21 protein expression and promoting the apoptotic protein in a p53-dependent and independent manner.
| S-EPMC9808967 | biostudies-literature
Project description:TP53 is a critical tumor-suppressor gene that is mutated in more than half of all human cancers. Mutations in TP53 not only impair its antitumor activity, but also confer mutant p53 protein oncogenic properties. The p53-targeted therapy approach began with the identification of compounds capable of restoring/reactivating wild-type p53 functions or eliminating mutant p53. Treatments that directly target mutant p53 are extremely structure and drug-species-dependent. Due to the mutation of wild-type p53, multiple survival pathways that are normally maintained by wild-type p53 are disrupted, necessitating the activation of compensatory genes or pathways to promote cancer cell survival. Additionally, because the oncogenic functions of mutant p53 contribute to cancer proliferation and metastasis, targeting the signaling pathways altered by p53 mutation appears to be an attractive strategy. Synthetic lethality implies that while disruption of either gene alone is permissible among two genes with synthetic lethal interactions, complete disruption of both genes results in cell death. Thus, rather than directly targeting p53, exploiting mutant p53 synthetic lethal genes may provide additional therapeutic benefits. Additionally, research progress on the functions of noncoding RNAs has made it clear that disrupting noncoding RNA networks has a favorable antitumor effect, supporting the hypothesis that targeting noncoding RNAs may have potential synthetic lethal effects in cancers with p53 mutations. The purpose of this review is to discuss treatments for cancers with mutant p53 that focus on directly targeting mutant p53, restoring wild-type functions, and exploiting synthetic lethal interactions with mutant p53. Additionally, the possibility of noncoding RNAs acting as synthetic lethal targets for mutant p53 will be discussed.
| S-EPMC8480024 | biostudies-literature
Project description:The tumor suppressor p53 plays a critical role to preserve DNA fidelity from diverse insults through the regulation of cell-cycle checkpoints, DNA repair, senescence and apoptosis. The TP53 is the most frequently inactivated gene in human cancers. This leads to the production of mutant p53 proteins that loose wild-type p53 tumor suppression functions and concomitantly acquire new oncogenic properties among which deregulated cell proliferation, increased chemoresistance, disruption of tissue architecture, promotion of migration, invasion and metastasis and several other pro-oncogenic activities. Mouse models show that the genetic reconstitution of the wild type p53 tumor suppression functions rescues tumor growth. This strongly supports the notion that either restoring wt-p53 activity or inhibiting mutant p53 oncogenic activity could provide an efficient strategy to treat human cancers. In this review we briefly summarize recent advances in the study of small molecules and compounds that subvert oncogenic activities of mutant p53 protein into wt-p53 tumor suppressor functions. We highlight inhibitors of signaling pathways aberrantly modulated by oncogenic mutant p53 proteins as promising therapeutic strategies. Finally, we consider the clinical applications of compounds targeting mutant p53 and the use of currently available drugs in the treatment of tumors expressing mutant p53 proteins.
| S-EPMC5815234 | biostudies-literature
Project description:Human papillomavirus (HPV)-positive tonsil cancer has a better prognosis than HPV-negative tonsil cancer. Deintensification strategies to reduce or avoid radiotherapy (RT) for patients with HPV-associated tonsil cancer have been suggested. This study investigated the treatment outcomes of patients with HPV-associated tonsil cancer and suggested RT deintensification strategies. A cohort of 374 patients with HPV-associated tonsil cancer treated with primary surgery or RT between 2008 and 2020 was retrospectively evaluated. Survival and locoregional control rates after primary surgery or RT were analyzed, and propensity score matching was performed to adjust for clinical factors. Pearson's chi-square or Fisher's exact test was used to compare categorical variables, and Student's t-test was used to compare continuous variables. The Kaplan-Meier method and log-rank test were used to assess overall survival, progression-free survival, and locoregional failure (LRF). No significant differences in survival or LRF were observed between the primary surgery and RT groups. Subgroup analysis was conducted for patients who underwent primary surgery. Advanced pathological N stage, negative contralateral nodes at diagnosis, abutting or positive surgical margins, and no adjuvant RT were independent risk factors for LRF. Advanced pathological T stage was an independent risk factor for LRF in patients who underwent primary surgery without subsequent adjuvant RT. None of the patients with pathological complete remission (CR) after induction chemotherapy died or experienced LRF. Our study revealed that the outcomes of primary surgery and primary RT in HPV-positive tonsil cancer were similar after adjusting for clinical factors. Primary RT might be considered instead of surgery in patients with advanced pathological T stage. In the case of pathological CR after induction chemotherapy, deintensification for adjuvant RT should be considered.
| S-EPMC9764715 | biostudies-literature
Project description:Over the past 40 years, p53 has been the most widely studied protein in cancer biology. Originally thought to be an oncogene due to its stabilization in many cancers, it is now considered to be one of the most critical tumor suppressors in a cell's ability to combat neoplastic transformation. Due to its critical roles in apoptosis, cell-cycle arrest, and senescence, TP53 deletions and mutations are commonly observed and are often a portent of treatment failures and poor clinical outcomes. This is particularly true in chronic lymphocytic leukemia (CLL), as patients with p53 alterations have historically had dismal outcomes. As such, the tremendous efforts made to better understand the functions of p53 in CLL have contributed substantially to recent advances in treating patients with p53-pathway-deficient CLL.
| S-EPMC6896129 | biostudies-literature
Project description:In the late 1990s, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF-family, started receiving much attention for its potential in cancer therapy, due to its capacity to induce apoptosis selectively in tumour cells in vivo. TRAIL binds to its membrane-bound death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) inducing the formation of a death-inducing signalling complex (DISC) thereby activating the apoptotic cascade. The ability of TRAIL to also induce apoptosis independently of p53 makes TRAIL a promising anticancer agent, especially in p53-mutated tumour entities. Thus, several so-called TRAIL receptor agonists (TRAs) were developed. Unfortunately, clinical testing of these TRAs did not reveal any significant anticancer activity, presumably due to inherent or acquired TRAIL resistance of most primary tumour cells. Since the potential power of TRAIL-based therapies still lies in TRAIL's explicit cancer cell-selectivity, a desirable approach going forward for TRAIL-based cancer therapy is the identification of substances that sensitise tumour cells for TRAIL-induced apoptosis while sparing normal cells. Numerous of such TRAIL-sensitising strategies have been identified within the last decades. However, many of these approaches have not been verified in animal models, and therefore potential toxicity of these approaches has not been taken into consideration. Here, we critically summarise and discuss the status quo of TRAIL signalling in cancer cells and strategies to force tumour cells into undergoing apoptosis triggered by TRAIL as a cancer therapeutic approach. Moreover, we provide an overview and outlook on innovative and promising future TRAIL-based therapeutic strategies.
| S-EPMC6521007 | biostudies-literature
Project description:ObjectivesTo evaluate the clinical curative effects and toxicity of recombinant human adenovirus-p53 injection (rAd-p53) plus chemotherapy (CT), radiotherapy (RT), or concurrent chemoradiotherapy (CRT) for the treatment of cervical cancer.MethodsWe identified 14 eligible studies in the PubMed, Web of Science, Cochrane Library, Embase, CNKI, Wangfangdate, CBM, and VIP databases from their inception to May 2021 and performed meta-analyses using RevMan version 5.3.ResultsThis analysis included 14 studies involving 737 patients. The results of the meta-analysis results showed significantly improved complete remission (odds ratio [OR] = 2.54, 95% confidence interval [CI]: 1.74-3.70, p < 0.00001), partial remission (OR = 1.56, 95% CI: 1.14-2.14, p = 0.006), and object response (OR = 4.47, 95% CI: 3.02-6.60, p < 0.00001) rates in the rAd-p53 combination therapy group compared to those in the CT/RT/CRT group. The results of subgroup analyses of CT/RT/CRT were consistent with the overall results. Regarding the incidence of adverse reactions, only the occurrence rate of fever (OR = 18.21, 95% CI: 10.54-31.47, p < 0.00001) in the rAd-p53 combination group was higher than that in the CT/RT/CRT group. No other significant differences were observed in other adverse reactions.ConclusionRAd-p53 combined with CT/RT/CRT for the treatment of cervical cancer showed significant advantages in efficacy and safety compared to those in the CT/RT/CRT group. Therefore, rAd-p53 has great potential as an effective therapy for cervical cancer.Systematic review registrationhttps://inplasy.com/inplasy-2021-5-0058/.
| S-EPMC8558497 | biostudies-literature