Antiangiogenic Effects of Noscapine Enhance Radioresponse for GL261 Tumors

Abstract

Purpose-To determine whether the tubulin-binding drug noscapine could enhance radiosensitivity of GL261 glioma tumors by inhibiting tumor angiogenesis.Methods and Materials-The human T98G and murine GL261 glioma cell lines treated with noscapine, radiation, or both were assayed for clonogenic survival. Mice with established GL261 hind limb tumors were treated with noscapine, radiation or both to evaluate the effect of noscapine on radioresponse. In a separate experiment with the same treatment groups, 7 days after radiation tumors were resected and immunostained to measure proliferation rate, apoptosis and angiogenic activity.Results-Noscapine reduced clonogenic survival without enhancement of radiosensitivity in vitro. Noscapine combined with radiation significantly increased tumor growth delay: 5, 8, 13, 18 days for control, noscapine alone, radiation alone, and the combination treatment, respectively (p < 0.001). To assess the effect of the combination of noscapine plus radiation on the tumor vasculature, tubule formation by the murine endothelial 2H11 cells was tested. Noscapine with radiation significantly inhibited tubule formation compared with radiation alone. By immunohistochemistry, tumors treated with the combination of noscapine plus radiation showed a decrease in BrdU incorporation, an increase in apoptosis by TUNEL and a decrease in tumor vessel density compared with tumors treated with radiation alone. Conflict of interest: none.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conclusion-Noscapine enhanced the sensitivity of GL261 glioma tumors to radiation resulting in a significant tumor growth delay. These findings are clinically relevant, particularly in view of the mild toxicity profile of this drug. NIH Public Access

Noscapine chemosensitization enhances docetaxel anticancer activity and nanocarrier uptake in triple negative breast cancer

“…Our results highlight the dire need to explore the underlying mechanisms of increasing DTX anticancer effect after Nos chemo-sensitization. Several studies have suggested that Nos induces multiple proapoptotic responses that induce apoptosis against variety of cancer cells [9,14,15,18]. Previously, our lab also reported the synergistic activity between Nos with cisplatin and gemcitabine in A549 and H460 lung cancer cells [9,19].…”

“…Multiple investigations have shown that Nos acts though various mechanisms including its ability to inhibit microtubule assembly [12], suppress expression of hypoxia-inducible factor-1α [13], induce p21 and p53 [14], induce apoptosis-inducing factor (AIF) [15], activate c-Jun-N-terminal kinase (JNK) [16] and repress bcl-2 [10]. It has been reported that Nos can efficiently inhibit the growth of both paclitaxel-sensitive and paclitaxel-resistant ovarian cancer cells [16], suggesting that Nos may mediate anticancer effects though other mechanisms.…”

17 AAG for HSP90 Inhibition in Cancer – From Bench to Bedside

“…17-AAG was studied in vitro and in vivo (established intracranial tumors) using GL261 murine model of glioma. It caused a G 2 phase arrest in glioma cells along with downregulation of cyclin B1 and statistically significant volume reduction in intracranial tumors when compared with controls [53]. The combination of gefitinib (tyrosine kinsase inhibitor targeting EGFR) with 17-AAG has shown a synergistic cytotoxic effect when exposed together to multiple glioma cell lines [54].…”

DC vaccination with anti-CD25 treatment leads to long-term immunity against experimental glioma

“…26 The GL261 glioma model has been characterized in depth by others and has been widely used to test experimental treatment strategies. [27][28][29][30][31][32] We recently published an extensive validation study on the use of in vivo bioluminescence (BLI) for the monitoring of DC immunotherapy in this model. 21 Since GL261 tumor cells are considered moderately immunogenic, they can be used for immunotherapeutic studies.…”