Oxymatrine Attenuates Tumor Growth and Deactivates STAT5 Signaling in a Lung Cancer Xenograft Model.

Young Yun Jung,Kwang Seok Ahn,Chulwon Kim,Ojas A Namjoshi,Bruce E Blough,Muthu K Shanmugam,Jong Hyun Lee,Gautam Sethi,Acharan S Narula

doi:10.3390/cancers11010049

Young Yun Jung, Kwang Seok Ahn + Show 7 more

Open Access

https://doi.org/10.3390/cancers11010049

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Abstract

Oxymatrine (OMT) is a major alkaloid found in radix Sophorae flavescentis extract and has been reported to exhibit various pharmacological activities. We elucidated the detailed molecular mechanism(s) underlying the therapeutic actions of OMT in non-small cell lung cancer (NSCLC) cells and a xenograft mouse model. Because the STAT5 signaling cascade has a significant role in regulating cell proliferation and survival in tumor cells, we hypothesized that OMT may disrupt this signaling cascade to exert its anticancer effects. We found that OMT can inhibit the constitutive activation of STAT5 by suppressing the activation of JAK1/2 and c-Src, nuclear localization, as well as STAT5 binding to DNA in A549 cells and abrogated IL-6-induced STAT5 phosphorylation in H1299 cells. We also report that a sub-optimal concentration of OMT when used in combination with a low dose of paclitaxel produced significant anti-cancer effects by inhibiting cell proliferation and causing substantial apoptosis. In a preclinical lung cancer mouse model, OMT when used in combination with paclitaxel produced a significant reduction in tumor volume. These results suggest that OMT in combination with paclitaxel can cause an attenuation of lung cancer growth both in vitro and in vivo.

Highlights

Non-small cell lung cancer (NSCLC) is the most common and lethal cancer worldwide, affecting both men and women [1,2]
Several previous studies have shown that STAT5 plays a significant role in regulating tumor survival and proliferation [22,31,88,89,90]
We tested whether OMT can regulate constitutive STAT5 activation on A549 lung cancer cells

Summary

Introduction

Non-small cell lung cancer (NSCLC) is the most common and lethal cancer worldwide, affecting both men and women [1,2]. NSCLC is more common in women and in East Asia is often associated with environmental factors such as exposure to occupational carcinogens, second-hand smoke, pollution, and genetic susceptibility [2,4,5,6,7,8,9]. Cancers 2019, 11, 49 and significant up- or downregulation of gene expression in Kirsten rat sarcoma (KRAS) and epidermal growth factor receptor (EGFR) [2]. Current treatments for advanced lung cancer include chemotherapy, targeted therapies, and surgical removal of tumor followed by radiation therapy [10]. The existing treatment modalities exhibit serious side effects in patients. The identification and development of novel and efficient drugs from alternative sources such as Mother Nature are urgently required [11,12,13,14,15,16,17,18,19,20,21]

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