Triptolide represses oral cancer cell proliferation, invasion, migration, and angiogenesis in co-inoculation with U937 cells

Cheng-Yu Yang,Gu-Jiun Lin,Yuan-Wu Chen,Huey-Kang Sytwu,Kuo-Hsing Ma,Cheng-Chih Hsieh,Yi-Shing Shieh,Chih-Kung Lin,Shing-Hwa Huang

doi:10.1007/s00784-016-1808-1

Abstract

ObjectivesAdvanced oral cancer is a major public health concern because of a lack of effective prevention and treatment. Triptolide (TPL), a diterpenoid triepoxide derived from the Chinese herb Tripterygium wilfordii, has been demonstrated to possess strong anticancer properties. In this study, we investigated whether TPL exerts anticancer effects on the tumor microenvironment of head and neck squamous cell carcinoma (HNSCC).Materials and methodsHuman macrophage-like U937 cells were co-inoculated with oral cancer SAS cells in a noncontact transwell coculture system. Cytokine expression was detected using ELISA, and cell proliferation was detected using methylene blue. RNA levels were detected using qPCR. Protein levels were detected using Western blot analysis. In vivo experiments involved using xenografted NOD/SCID mice.ResultsOur results demonstrated that TPL inhibited the growth of SAS cells co-inoculated with U937 cells in vitro and in vivo. TPL inhibited the invasion, migration ability, and angiogenesis of SAS cells co-inoculated with U937 cells. Expression of cytokines IL-6, IL-8, and TNF-α was induced by co-inoculation, but TPL repressed their expression.ConclusionTPL suppressed the expression of cytokines IL-6, IL-8, and TNF-α, as well as tumor growth, invasion, migration, and angiogenesis in the co-inoculation of human tongue cancer cells with macrophage-like U937 cells.Clinical relevanceTPL is a potential candidate among novel chemotherapeutic agents or adjuvants for modulating tumor-associated macrophages in a tumor microenvironment of HNSCC.

Highlights

Oral squamous cell carcinoma (OSQCC), the most common of oral malignancies, is a type of head and neck squamous cell carcinoma (HNSCC), which is the sixth most prevalent malignancy worldwide and the third most common cancer in developing countries [1,2,3,4,5]
To further assess the therapeutic effect of TPL in vivo, we established a xenograft tumor model in which SAS oral cancer cells were co-inoculated with phorbol 12-myristate 13acetate (PMA)-treated U937 cells
These results revealed that TPL was effective against SAS co-inoculated with macrophage-like U937 cells both in vitro and in vivo

Summary

Introduction

Oral squamous cell carcinoma (OSQCC), the most common of oral malignancies, is a type of head and neck squamous cell carcinoma (HNSCC), which is the sixth most prevalent malignancy worldwide and the third most common cancer in developing countries [1,2,3,4,5]. Concurrent chemoradiotherapy has exhibited efficacy for organ preservation in head and neck cancer, but has resulted in limited improvement in survival rates. Discovering potential therapeutic drugs for advanced oral cancer is paramount. Macrophages are widely distributed in the body, being produced by the differentiation of monocytes in tissues. Macrophages participate in both innate and adaptive immunity of vertebrate animals. Macrophages are often observed to infiltrate the extracellular space around cancer cells and are designated as tumor-associated macrophages (TAMs) [6, 7]. A study revealed that the increase in TAMs in patients suffering from head and neck cancer is associated with an increase in histopathological grades and tumor angiogenesis [8]

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