Glioblastomas (GBM) are heterogeneous tumors with high metabolic plasticity. Their poor prognosis is linked to the presence of glioblastoma stem cells (GSC), which support resistance to therapy, notably to temozolomide (TMZ). Mesenchymal stem cells (MSC) recruitment to GBM contributes to GSC chemoresistance, by mechanisms still poorly understood. Here, we provide evidence that MSCs transfer mitochondria to GSCs through tunneling nanotubes, which enhances GSCs resistance to TMZ. More precisely, our metabolomics analyses reveal that MSC mitochondria induce GSCs metabolic reprograming, with a nutrient shift from glucose to glutamine, a rewiring of the tricarboxylic acid cycle from glutaminolysis to reductive carboxylation and increase in orotate turnover as well as in pyrimidine and purine synthesis. Metabolomics analysis of GBM patient tissues at relapse after TMZ treatment documents increased concentrations of AMP, CMP, GMP, and UMP nucleotides and thus corroborate our in vitro analyses. Finally, we provide a mechanism whereby mitochondrial transfer from MSCs to GSCs contributes to GBM resistance to TMZ therapy, by demonstrating that inhibition of orotate production by Brequinar (BRQ) restores TMZ sensitivity in GSCs with acquired mitochondria. Altogether, these results identify a mechanism for GBM resistance to TMZ and reveal a metabolic dependency of chemoresistant GBM following the acquisition of exogenous mitochondria, which opens therapeutic perspectives based on synthetic lethality between TMZ and BRQ.Significance: Mitochondria acquired from MSCs enhance the chemoresistance of GBMs. The discovery that they also generate metabolic vulnerability in GSCs paves the way for novel therapeutic approaches.

Lepidium sativum L. is a common herb distributed worldwide, used as a food ingredient and therapeutic agent in traditional medicine for treating health-related disorders. L. sativum and its extracts have been described to possess numerous biological activities including antimicrobial, antidiabetic, antioxidant, antidiarrheal, anticancer, and numerous health-promoting effects in in vivo and in vitro studies. The purpose of this review is to summarize the findings describing important biological functions and therapeutic effects of L. sativum in various cell lines and animal models. In this review, the English-language articles were gathered from electronic databases including Web of Science, PubMed and Google Scholar with no time limit applied to any database. The search terms used in this review include, “Lepidium sativum L.” and/or “chemical composition”, “health benefits”, “antimicrobial”, “antioxidant”, “anticancer”, “diuretic”, “nephro-protection”, “antidiarrheal”, “antidiabetic”, “anti-asthmatic”, “neuroprotection”, “metabolic”, “bone fracture”, and “reproductive performance”. Additional and eligible studies were collected from reference lists of appropriate articles. The information presented will be helpful to attract more interest toward medicinal plants by defining and developing novel clinical applications and new drug formulations in the future. Pre-clinical studies showed that L. sativum possesses potent health-promoting effects involving various molecular mechanisms. Taken all together, data suggested that identified herbal plants such as L. sativum, can be exploited as nutritional and therapeutic agents to combat various ailments. Despite much research in this field, further comprehensive in vitro/in vivo studies and clinical trials are needed to identify the mechanisms underlying the biological and therapeutic activities of L. sativum.

Methylsulfonylmethane (MSM) is an organic sulfur-containing compound which has been used as a dietary supplement for osteoarthritis. MSM has been shown to reduce oxidative stress and inflammation, as well as exhibit apoptotic or anti-apoptotic effects depending on the cell type or activating stimuli. However, there are still a lot of unknowns about the mechanisms of actions of MSM. In this study, MSM was tested on colon cancer cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis revealed that MSM inhibited cell viability and increased apoptotic markers in both HCT-116 p53 +/+ and HCT-116 p53 −/− colon cancer cells. Increased poly (ADP-ribose) polymerase (PARP) fragmentation and caspase-3 activity by MSM also supported these findings. MSM also modulated the expression of various apoptosis-related genes and proteins. Moreover, MSM was found to increase c-Jun N-terminal kinases (JNK) phosphorylation in both cell lines, dose-dependently. In conclusion, our results show for the first time that MSM induces apoptosis in HCT-116 colon cancer cells regardless of their p53 status. Since p53 is defective in >50% of tumors, the ability of MSM to induce apoptosis independently of p53 may offer an advantage in anti-tumor therapy. Moreover, the remarkable effect of MSM on Bim, an apoptotic protein, also suggests its potential use as a novel chemotherapeutic agent for Bim-targeted anti-cancer therapies.