Evaluating the Combined Effect of a Choline Kinase Inhibitor and Temozolomide Therapy in a Mouse Model of Glioblastoma Using ¹H MR Spectroscopy and IVIM‐DWI

Article

作者: Maguire, Mahon L. ; Moothanchery, Mohesh ; Bhaduri, Sourav ; Ressel, Lorenzo ; Gash, Elisabeth Non ; Poptani, Harish ; Alrashidi, Tareq ; Ball, Christopher

ABSTRACT:

This study evaluated the therapeutic efficacy of combining a choline kinase alpha (ChoKα) inhibitor, MN58b, and temozolomide (TMZ) in a syngeneic GL261 glioblastoma (GBM) mouse model. It used MR spectroscopy (MRS) and intravoxel incoherent motion diffusion‐weighted imaging (IVIM‐DWI) to assess metabolic and microstructural changes within the tumor. Fifty‐two C57BL/6 mice had GL261 cells implanted intracranially and were divided into four groups: saline control, MN58b, TMZ, and MN58b + TMZ (n = 16, 14, 11, and 11, respectively). Treatments were administered for 5 days, starting 10 days post‐implantation. MRI scans (T2‐weighted, MRS, IVIM‐DWI) were performed at baseline, during treatment (Day 3), and post‐treatment (Day 6). The histological analysis evaluated the tumor mitotic index and caspase‐3 expression. Combination therapy with MN58b + TMZ significantly reduced tCho/NAA, Lip + Lac/tCr, and mI/tCr, suggesting decreased phosphocholine synthesis and tumor proliferation. IVIM‐DWI showed a significant increase in diffusion coefficient (D) values, indicating reduced cell density. Metabolic changes detected by 1H MRS were observable as early as Day 3 post‐treatment initiation, preceding microstructural alterations detected by IVIM‐DWI at Day 6. This suggests that MRS biomarkers may serve as early indicators of treatment response, facilitating timely therapeutic decisions. Histology confirmed a significantly lower mitotic index relative to control tumors in the combination treatment group. Significantly prolonged survival with combination therapy was noted relative to other groups. However, the tumor volumes were not significantly different between groups. Combination therapy targeting ChoKα and cellular proliferation with MN58b and TMZ outperformed individual treatments for GBM, warranting further exploration. The integration of MN58b with the current standard of care (TMZ + RT) might further enhance the therapeutic outcomes. MRS and IVIM‐DWI demonstrate potential utility as non‐invasive imaging markers for treatment monitoring.

2021-09-22·JCI insight1区 · 医学

Autophagy-mitophagy induction attenuates cardiovascular inflammation in a murine model of Kawasaki disease vasculitis

1区 · 医学

ArticleOA

作者: Stotland, Aleksandr ; Moreira, Debbie ; Sanchez-Lopez, Elsa ; Zemmour, David ; Ozdemir, Asli B ; Marek-Iannucci, Stefanie ; Crother, Timothy R ; Parker, Sarah ; Van Eyk, Jennifer ; Abe, Masanori ; Arditi, Moshe ; Rivas, Magali Noval ; Karin, Michael ; Lane, Malcolm ; Fishbein, Michael C ; Shimada, Kenichi ; Gottlieb, Roberta A ; Porritt, Rebecca A ; Gomez, Angela C ; Lee, Youngho

Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3-IL-1β pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell-specific deletion of Atg16l1 and global Parkin-/- significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1-/- mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.

2017-03-07·Oncotarget

Near infrared fluorescent imaging of choline kinase alpha expression and inhibition in breast tumors

Article

作者: Arlauckas, Sean P. ; Popov, Anatoliy V. ; Poptani, Harish ; Kumar, Manoj ; Delikatny, Edward J.

Choline kinase alpha (ChoKα) overexpression is associated with an aggressive tumor phenotype. ChoKα inhibitors induce apoptosis in tumors, however validation of their specificity is difficult in vivo. We report the use of optical imaging to assess ChoKα status in cells and in vivo using JAS239, a carbocyanine-based ChoKα inhibitor with inherent near infrared fluorescence. JAS239 attenuated choline phosphorylation and viability in a panel of human breast cancer cell lines. Antibody blockade prevented cellular retention of JAS239 indicating direct interaction with ChoKα independent of the choline transporters and catabolic choline pathways. In mice bearing orthotopic MCF7 breast xenografts, optical imaging with JAS239 distinguished tumors overexpressing ChoKα from their empty vector counterparts and delineated tumor margins. Pharmacological inhibition of ChoK by the established inhibitor MN58b led to a growth inhibition in 4175-Luc+ tumors that was accompanied by concomitant reduction in JAS239 uptake and decreased total choline metabolite levels as measured using magnetic resonance spectroscopy. At higher therapeutic doses, JAS239 was as effective as MN58b at arresting tumor growth and inducing apoptosis in MDA-MB-231 tumors, significantly reducing tumor choline below baseline levels without observable systemic toxicity. These data introduce a new method to monitor therapeutically effective inhibitors of choline metabolism in breast cancer using a small molecule companion diagnostic.

100 项与 MN58b 相关的药物交易

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