bims-midomi 2025-05-18 papers

Biochem Biophys Res Commun. 2025 May 10. pii: S0006-291X(25)00658-8. [Epub ahead of print]769 151944

Effects of n-Myc and c-Myc on the expression of p53 family members and their transcriptional targets in human neuroblastoma cells.

Alexander Nazarov, Sergey Parfenyev, Oleg Shuvalov, Ksenia Frolova, Elizaveta Naminat, Ivan Nevzorov, Alexey Petukhov, Natalia Karpova, Olga Fedorova, Nikolai Barlev, Alexandra Daks.

Neuroblastoma (NB) is an embryonic malignancy causing 15 % of pediatric cancer fatalities. Amplification of the MYCN gene is one of the major NB drivers and biomarkers of high-risk NB. MYCN amplification is associated with high p53-coding gene expression and decreased survival rates in patients. Importantly, only 1-2 % of NB cases harbor TP53 mutations. Moreover, both high TP53 and low MYC expression levels are unfavorable prognostic markers for NB patients, which is not typical for most types of tumors. In this study we analyzed the effect of MYCN amplification on the expression of genes coding p53 family members - TP63 and TP73. We show that, unlike TP53, TP63 and TP73 levels are higher in MYCN-amplified samples. Furthermore, high TP63 and TP73 expression is a favorable prognostic marker for NB patients' survival. That MDM2 inhibition contributes to p53 stabilization and augments the cytotoxic activity of doxorubicin in NB cells prompted us to test the cytotoxic effects of three small-molecule inhibitors of MDM2 that differ in their mechanisms: Nutlin-3a, Mel23, and SP-141. Our results showed that despite the same target, MDM2, these compounds displayed different cytotoxic effects and synergy with doxorubicin on two widely used NB cell lines, IMR-32 and SH-SY5Y that vary in the amount of MDM2 expression. Collectively, our results suggest that except Nutlin-3a, the other two inhibitors, Mel23 and SP-141, employ additional Mdm2-independent mechanisms of cytotoxicity in NB cells that warrants further investigation.

Keywords: MDM2; MYC; MYCN; Neuroblastoma; p53; p63

DOI: https://doi.org/10.1016/j.bbrc.2025.151944

Curr Cancer Drug Targets. 2025 May 12.

The Association of KRAS and P53 Gene Mutations and MDM2 Expression with the Occurrence of Colorectal Cancer.

Hany A Al-Hussaniy, Amjad I Oraibi, Zahraa Salam Al-Tameemi, Ali Hikmat Alburghaif, Meena Akeel Naji, Fatima Akeel Naji.

BACKGROUND: Colorectal cancer (CRC) encompasses various cancers located in the rectosigmoid junction, rectum, and anus, as well as parts of the colon. Globally, CRC is the second leading cause of cancer-related mortality and the third most prevalent malignan-cy. The KRAS oncogene was found to be mutated in 30 to 50% of CRC cases, leading to dysregulated cellular functions. Furthermore, the connection between KRAS and P53 gene mutations and the incidence of both colorectal and breast cancer remains an area of interest.
METHOD: This comprehensive narrative review was carried out by mining data from recog-nized databases, such as PubMed, Google Scholar, and ResearchGate. The purpose was to extensively explore and understand the association between the KRAS and P53 gene muta-tions and the prevalence of colorectal and breast cancers.
RESULTS: The mutation in the KRAS oncogene has been identified as a key player in cellular signaling pathways, including MAPK, PI3K, and PLD. Despite extensive research, gene therapies targeting these mutations have seen limited success, especially in codons 12, 13, 61, and 143.
CONCLUSION: Mutations in the KRAS and P53 genes, along with aberrant MDM2 expression, play pivotal roles in the onset and progression of colorectal cancer by disrupting key cellular signaling pathways, such as MAPK, PI3K, and PLD. Despite advancements in understand-ing these mechanisms, current gene therapy approaches have shown limited success, particu-larly in targeting KRAS codon mutations. This underscores the urgent need for innovative therapeutic strategies and further research to develop effective treatments for colorectal can-cer and its potential links to other malignancies, such as breast cancer.

Keywords: KRAS gene mutations; P53 gene mutations; colorectal cancer; gene therapy.

DOI: https://doi.org/10.2174/0115680096349198250407100724

Cancers (Basel). 2025 May 07. pii: 1586. [Epub ahead of print]17(9):

Unraveling Venetoclax Resistance: Navigating the Future of HMA/Venetoclax-Refractory AML in the Molecular Era.

Theodora Chatzilygeroudi, Theodoros Karantanos, Vasiliki Pappa.

Acute myeloid leukemia (AML) has traditionally been linked to a poor prognosis, particularly in older patients who are ineligible for intensive chemotherapy. The advent of Venetoclax, a powerful oral BH3 mimetic targeting anti-apoptotic protein BCL2, has significantly advanced AML treatment. Its combination with the hypomethylating agent azacitidine (AZA/VEN) has become a standard treatment for this group of AML patients, demonstrating a 65% overall response rate and a median overall survival of 14.7 months, compared to 22% and 8 months with azacitidine monotherapy, respectively. However, resistance and relapses remain common, representing a significant clinical challenge. Recent studies have identified molecular alterations, such as mutations in FLT3-ITD, NRAS/KRAS, TP53, and BAX, as major drivers of resistance. Additionally, other factors, including metabolic changes, anti-apoptotic protein expression, and monocytic or erythroid/megakaryocytic differentiation status, contribute to treatment failure. Clinical trials are exploring strategies to overcome venetoclax resistance, including doublet or triplet therapies targeting IDH and FLT3 mutations; novel epigenetic approaches; menin, XPO1, and MDM2 inhibitors; along with immunotherapies like monoclonal antibodies and antibody-drug conjugates. A deeper understanding of the molecular mechanisms of resistance through single-cell analysis will be crucial for developing future therapeutic strategies.

Keywords: AML; clinical trials; resistance; venetoclax

DOI: https://doi.org/10.3390/cancers17091586

Front Pharmacol. 2025 ;16 1572906

Resveratrol targeting MDM2/P53/PUMA axis to inhibit colonocyte apoptosis in DSS-induced ulcerative colitis mice.

Rui Tang, Ling Jiang, Quan Ji, Pengyuan Kang, Yuan Liu, Pengyu Miao, Xiaofan Xu, Mingxi Tang.

Background: Resveratrol, a naturally occurring polyphenolic compound found in grapes, berries, and traditional medicinal plants like Polygonum cuspidatum, has been used for centuries in traditional medicine systems for its anti-inflammatory, antioxidant, and cardioprotective properties. Ulcerative colitis (UC), a chronic inflammatory bowel disease, is characterized by intestinal barrier disruption due to excessive colonocyte apoptosis, leading to increased permeability and inflammation. Targeting apoptosis is a critical therapeutic strategy for UC.
Aim of the study: This study aims to investigate the therapeutic potential of Resveratrol in ulcerative colitis (UC) by targeting excessive colonocyte apoptosis and intestinal barrier dysfunction. Specifically, we seek to elucidate the mechanisms through which Resveratrol modulates apoptosis-related pathways and evaluate its efficacy in restoring intestinal homeostasis and mitigating UC progression in both in vivo and in vitro models.
Materials and Methods: We used dextran sulfate sodium (DSS) to induce UC in a mouse model. Colonic damage was assessed through colonic length measurement, histological examination, and immunofluorescence staining. Single-cell sequencing was employed to explore changes in the colonic immune microenvironment and cellular signaling pathways after Resveratrol treatment. In vitro, colonocytes isolated from healthy mouse colonic tissue were exposed to TGF-β to induce apoptosis. DNA fragmentation, mitochondrial membrane potential, and annexin V/propidium iodide staining were used to assess apoptosis. Additionally, we employed an Adeno-Associated Virus system to overexpress MDM2 in the colon and evaluate its protective role in DSS-induced UC.
Results: Resveratrol treatment effectively repaired colonic damage in the UC mouse model by significantly increasing colon length, reducing inflammatory cell infiltration, and mitigating mucosal injury. Single-cell sequencing revealed that Resveratrol primarily targeted colonocytes, decreasing genes related to apoptosis and the P53 pathway. In vitro, Resveratrol reduced DNA fragmentation, apoptotic cell populations, and increased mitochondrial membrane potential in a dose-dependent manner. Furthermore, Resveratrol increased MDM2 expression, inhibiting P53 and downstream pro-apoptotic signaling. Nutlin-3a, an MDM2 inhibitor, reversed the anti-apoptotic effects of Resveratrol. Overexpression of MDM2 in the colon protected against DSS-induced damage.
Conclusion: Resveratrol is an effective treatment for DSS-induced UC, primarily by inhibiting excessive apoptosis in colonocytes through the MDM2/P53/PUMA axis. MDM2 presents a promising therapeutic target for UC treatment.

Keywords: MDM2/P53/PUMA axis; apoptosis; colonocyte; resveratrol; ulcerative colitis

DOI: https://doi.org/10.3389/fphar.2025.1572906