Targeting gut microbial nitrogen recycling and cellular uptake of ammonium to improve bortezomib resistance in multiple myeloma.

The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In previous studies, we demonstrated that intestinal nitrogen-recycling bacteria are enriched in patients with MM. However, their role in MM relapse remains unclear. This study highlights the specific enrichment of Citrobacter freundii (C. freundii) in patients with relapsed MM. Through fecal microbial transplantation experiments, we demonstrate that C. freundii plays a critical role in inducing drug resistance in MM by increasing levels of circulating ammonium. The ammonium enters MM cells through the transmembrane channel protein SLC12A2, promoting chromosomal instability and drug resistance by stabilizing the NEK2 protein. We show that furosemide sodium, a loop diuretic, downregulates SLC12A2, thereby inhibiting ammonium uptake by MM cells and improving progression-free survival and curative effect scores. These findings provide new therapeutic targets and strategies for the intervention of MM progression and drug resistance.

The pharmacoepigenomic landscape of cancer cell lines reveals the epigenetic component of drug sensitivity.

Aberrant DNA methylation accompanies genetic alterations during oncogenesis and tumour homeostasis and contributes to the transcriptional deregulation of key signalling pathways in cancer. Despite increasing efforts in DNA methylation profiling of cancer patients, there is still a lack of epigenetic biomarkers to predict treatment efficacy. To address this, we analyse 721 cancer cell lines across 22 cancer types treated with 453 anti-cancer compounds. We systematically detect the predictive component of DNA methylation in the context of transcriptional and mutational patterns, i.e., in total 19 DNA methylation biomarkers across 17 drugs and five cancer types. DNA methylation constitutes drug sensitivity biomarkers by mediating the expression of proximal genes, thereby enhancing biological signals across multi-omics data modalities. Our method reproduces anticipated associations, and in addition, we find that the NEK9 promoter hypermethylation may confer sensitivity to the NEDD8-activating enzyme (NAE) inhibitor pevonedistat in melanoma through downregulation of NEK9. In summary, we envision that epigenomics will refine existing patient stratification, thus empowering the next generation of precision oncology.

Effect of Neoadjuvant Chemotherapy on Angiogenesis and Cell Proliferation of Breast Cancer Evaluated by Dynamic Enhanced Magnetic Resonance Imaging.

Background: Breast cancer is the uncontrolled proliferation of breast epithelial cells under the action of various carcinogenic factors. The evaluation of early efficacy of neoadjuvant chemotherapy for breast cancer is helpful to change the treatment plan in time. On this basis, dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) was used to evaluate the effects of neoadjuvant chemotherapy on angiogenesis and cell proliferation in breast cancer. Objective: To evaluate the effect of neoadjuvant chemotherapy on angiogenesis and cell proliferation of breast cancer by dynamic enhanced DCE-MRI. Method: 80 breast cancer patients were divided into the routine chemotherapy group (3 cycles) and neoadjuvant chemotherapy groups (3 cycles) of 40 cases each from January 2018 to June 2021. Based on conventional imaging, DCE-MRI was performed with Intera Achieva 3.0 TMR superconducting MR scanner before and after treatment. The quantitative indexes, MRI parameters, cell proliferation expression, and DCE-MRI angiogenesis were compared between the two groups. Result: The inhibition rate, Vepost, Ktranspre, ADC, Bax, Alexi, and Aurora in the neoadjuvant chemotherapy group were significantly higher than those in the conventional chemotherapy group (P < 0.05), while Kep, Ktrans, and Nek2 were significantly lower than those in the conventional chemotherapy group (P < 0.05). Vepre (cm3), Ktranspre (ml/min/100 cm3), and Ve had no significant difference (P > 0.05). Conclusion: The quantitative parameters, MRI parameters, proliferation, and expression of DCE-MRI in breast cancer patients with different chemotherapy regimens are quite different. They can be applied to the diagnosis of neoadjuvant chemotherapy in breast cancer patients with angiogenesis and cell proliferation.

Epigenetics of Triple-Negative Breast Cancer via Natural Compounds.

Triple-negative breast cancer (TNBC) is a highly resistant, lethal, and metastatic sub-division of breast carcinoma, characterized by the deficiency of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In women, TNBC shows a higher aggressive behavior with poor patient prognosis and a higher recurrence rate during reproductive age. TNBC is defined by the presence of epithelial- to-mesenchymal-transition (EMT), which shows a significant role in cancer progression. At the epigenetic level, TNBC is characterized by epigenetic signatures, such as DNA methylation, histone remodeling, and a host of miRNA, MiR-193, LncRNA, HIF- 2α, eEF2K, LIN9/NEK2, IMP3, LISCH7/TGF-ß1, GD3s, KLK12, mediated regulation. These modifications either are silenced or activate the necessary genes that are prevalent in TNBC. The review is based on epigenetic mediated mechanistic changes in TNBC. Furthermore, Thymoquinone (TQ), Regorafenib, Fangjihuangqi decoction, Saikosaponin A, and Huaier, etc., are potent antitumor natural compounds extensively reported in the literature. Further, the review emphasizes the role of these natural compounds in TNBC and their possible epigenetic targets, which can be utilized as a potential therapeutic strategy in the treatment of TNBC.

NEK2 Is an Effective Target for Cancer Therapy With Potential to Induce Regression of Multiple Human Malignancies.

Cancer is characterized by uncontrolled cell proliferation due to the aberrant activity of various proteins. Cell cycle-related proteins are thought to be important in several functions, such as proliferation, invasion and drug resistance in human malignancies. Never in mitosis gene A-related kinase 2 (NEK2) is a cell cycle-related protein. NEK2 is highly expressed in various tumor types and cancer cell lines. NEK2 expression is correlated with rapid relapse and poor outcome in multiple cancer types. Several researchers have demonstrated that NEK2 inhibition results in anticancer effects against many types of cancers, both in vitro and in vivo. Recent research strongly indicates the advantages of NEK2-targeted therapy for cancer. This review focuses on the current understanding of NEK2 in cancer and the rationale of a xenograft cancer model for cancer treatment. A possible therapeutic strategy, such as inhibitor and nucleic acid medicine targeting of NEK2, is also discussed.