Despite advances in the understanding of the molecular mechanisms underlying the basic biology and pathogenesis of pediatric central nervous system (CNS) malignancies, patients still have an extremely unfavorable prognosis. Over the years, a plethora of natural and synthetic compounds has emerged for the pharmacologic intervention of the NF-kB pathway, one of the most frequently dysregulated signaling cascades in human cancer with key roles in cell growth, survival, and therapy resistance. Here, we provide a review about the state-of-the-art concerning the dysregulation of this hub transcription factor in the most prevalent pediatric CNS tumors: glioma, medulloblastoma, and ependymoma. Moreover, we compile the available literature on the anti-proliferative effects of varied NF-kB inhibitors acting alone or in combination with other therapies in vitro, in vivo, and clinical trials. As the wealth of basic research data continues to accumulate, recognizing NF-kB as a therapeutic target may provide important insights to treat these diseases, hopefully contributing to increase cure rates and lower side effects related to therapy.

The multifaceted NF-kB: are there still prospects of its inhibition for clinical intervention in pediatric central nervous system tumors?

Human papillomaviruses (HPVs) are high-risk causative factors for HPV infection. This infection does not come alone; it is often seen with co-infection with other viruses and acts as a causative agent for several malignancies. The major purpose of this comprehensive study was to highlight some recent advances in biotechnology associated with HPV infection, including understanding its host interactions and cancerous progression. A systematic research strategy was used to gather data from recent, and the most advanced published electronic sources. The compiled data explain the recent understanding of biology, host–viral interaction cycles, co-infection with other viral diseases, and cellular transformation toward malignancies associated with HPV. In recent years, some vaccination protocols have been introduced in the form of live attenuated, subunit, and DNA-based vaccines. Moreover, some strategies of nanotechnology are being employed to synthesize drugs and vaccines with a whole new approach of plant-based products. The data are immense for the proposed research question, yet the need is to implement modern follow-up screening and modern therapeutics at the clinical level and to conduct wide-scale public awareness to lessen the HPV-related disease burden.

https://www.mdpi.com/2076-393X/11/1/102/pdf?version=1672562839

Tracking HPV Infection, Associated Cancer Development, and Recent Treatment Efforts—A Comprehensive Review

Eicosapentaenoic acid enhanced apoptotic and oxidant effects of cisplatin via activation of TRPM2 channel in brain tumor cells.

Tumor differentiation is a therapeutic strategy aimed at reactivating the endogenous differentiation program of cancer cells and inducing cancer cells to mature and differentiate into other types of cells. It has been found that a variety of natural small-molecule drugs can induce tumor cell differentiation both in vitro and in vivo. Relevant molecules involved in the differentiation process may be potential therapeutic targets for tumor cells. Compared with synthetic drugs, natural small-molecule antitumor compounds have the characteristics of wide sources, structural diversity and low toxicity. In addition, natural drugs with structural modification and transformation have relatively concentrated targets and enhanced efficacy. Therefore, using natural small-molecule compounds to induce malignant cell differentiation represents a more targeted and potential low-toxicity means of tumor treatment. In this review, we focus on natural small-molecule compounds that induce differentiation of myeloid leukemia cells, osteoblasts and other malignant cells into functional cells by regulating signaling pathways and the expression of specific genes. We provide a reference for the subsequent development of natural small molecules for antitumor applications and promote the development of differentiation therapy.

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Research Progress of Natural Small-Molecule Compounds Related to Tumor Differentiation

Simple Summary ONX-0914 (PR957) is a proteasome subunit beta type-8 (PSMB8)-selective inhibitor. Previous studies have shown that inhibiting PSMB8 expression in a glioblastoma reduces tumor progression and angiogenesis. This study shows that ONX-0914 inhibits glioblastoma cell proliferation and induces cell death through apoptosis and autophagy via p53. In a mouse xenograft model, TMZ-combined ONX-0914 reduced tumor progression. This is the first study to evaluate the ONX-0914 function in glioblastomas. Abstract Glioblastoma is believed to be one of the most aggressive brain tumors in the world. ONX-0914 (PR957) is a selective inhibitor of proteasome subunit beta type-8 (PSMB8). Previous studies have shown that inhibiting PSMB8 expression in glioblastoma reduces tumor progression. Therefore, this study aimed to determine whether ONX-0914 has antitumor effects on human glioblastoma. The results indicated that ONX-0914 treatment inhibited survival in LN229, GBM8401, and U87MG glioblastoma cells. Cell cycle analysis showed that ONX-0914 treatment caused cell cycle arrest at the G1 phase and apoptosis in glioblastoma cells. The protein expression of BCL-2 was reduced and PARP was cleaved after ONX-0914 treatment. Furthermore, the levels of p53 and phosphorylated p53 were increased by ONX-0914 treatment in glioblastoma cells. ONX-0914 also induced autophagy in glioblastoma cells. Furthermore, the p53 inhibitor pifithrin attenuated apoptosis but enhanced autophagy caused by ONX-0914. In an orthotopic mouse model, TMZ plus ONX-0914 reduced tumor progression better than the control or TMZ alone. These data suggest that ONX-0914 is a novel therapeutic drug for glioblastoma.

https://www.mdpi.com/2072-6694/14/22/5712/pdf?version=1669034674

ONX-0914 Induces Apoptosis and Autophagy with p53 Regulation in Human Glioblastoma Cells

Glioblastoma multiforme (GBM) is one of the most aggressive astrocytic tumors; it is resistant to most chemotherapeutic agents currently available and is associated with a poor patient survival. Thus, the development of new anticancer compounds is urgently required. Herein, we studied the molecular mechanisms of cell death induced by the experimental drugs resveratrol and MG132 or the antineoplastic drugs cisplatin and etoposide on a human GBM cell line (D54) and on primary cultured mouse astrocytes (PCMAs). Caspases, Bcl-2, inhibitors of apoptosis proteins (IAP) family members, and p53 were identified as potential molecular targets for these drugs. All drugs had a cytotoxic effect on D54 cells and PCMAs, with a similar inhibitory concentration (IC50) after 24 h. However, MG132 and cisplatin were more effective to induce apoptosis and autophagy than resveratrol and etoposide. Cell death by apoptosis involved the activation of caspases-3/7, -8, and -9, increased lysosomal permeability, LC3 lipidation, poly-(ADP-ribose) polymerase (PARP)-1 fragmentation, and a differential expression of genes related with apoptosis and autophagy like Mcl-1, Survivin, Noxa, LC3, and Beclin. In addition, apoptosis activation was partially dependent on p53 activation. Since experimental and antineoplastic drugs yielded similar results, further work is required to justify their use in clinical protocols.

Molecular mechanisms of cell death induced in glioblastoma by experimental and antineoplastic drugs: New and old drugs induce apoptosis in glioblastoma.

The aim is to determine the prevalence of active infection by herpes simplex virus type 2 (HSV-2) among Mexican women with high-risk human papillomavirus (HR-HPV) cervical infection, recruited from public gynecology and colposcopy services. In a cross-sectional study, HSV-2 antibodies, HSV-2 DNA, and HR-HPV DNA were quantified. Significant differences in HSV-2 seroprevalence and HSV-2 active infection rates were found between negative and positive HR-HPV cases. HSV-2 seroprevalence was 28.15% and 16.1% (P = .0001), while HSV-2 active infection rates were 6.83% and 0.62% (P = .001) for positive and negative HR-HPV groups, respectively. The risk of HSV-2 seropositivity was 1.7 times greater for HR-HPV-positive cases (P = .02). Similarly, HR-HPV-positive cases were nine times more likely to have an HSV-2 active infection than HR-HPV-negative cases (P = .03). High HSV-2/h-HPV coinfection rates were observed among women recruited from public gynecology and colposcopy services. The main factors related to an HSV-2 active infection are a history of risky sexual behavior and HR-HPV infection. The prevalence of HSV-2 active infection among positive HR-HPV subjects indicate that these infections constitute an important group of STIs in Mexico.

C O Contreras-Ochoa

Papers

Molecular mechanisms of cell death induced in glioblastoma by experimental and antineoplastic drugs: New and old drugs induce apoptosis in glioblastoma.

Prevalence of active infection by herpes simplex virus type 2 in patients with high-risk human papillomavirus infection: A cross-sectional study.