Abstract
The combination of chemotherapy with natural products is a common strategy to enhance anticancer effects while alleviating the dose-dependent adverse effects of cancer treatment. Oxymatrine (OMT) has been extensively reported as having anticancer activity. Doxorubicin (DOX) is a chemotherapeutic DNA-damaging agent used for the treatment of carcinoma. In this study, we investigated whether synergistic effects exist with the combination treatment with OMT and DOX using human colorectal cancer cell (CRC) lines and the potential mechanisms involved in in vitro and in vivo activities. The MTT and colony formation assay results showed that compared to either OMT or DOX monotherapy, the combination of OMT + DOX markedly inhibited the growth of HT-29 and SW620 cells. Wound healing assays showed significant inhibition of cell migration with co-treatment, supported by the change in E-cadherin and N-cadherin expressions in Western blotting. Furthermore, flow cytometry analysis revealed that OMT + DOX co-treatment enhanced cell apoptosis as a result of ROS generation, whereas NAC attenuated OMT + DOX–induced apoptosis. Similarly, the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9, and the ratio of Bax/Bcl-2) were determined by Western blotting, which showed that the expressions of these markers were notably increased in the co-treatment group. Furthermore, co-administration of a low dose of DOX and OMT inhibited xenograft tumor growth in a dose-dependent manner. TUNEL assay and Ki67 staining images indicated more apoptosis and less proliferation occurred in OMT plus DOX-treated xenograft tumors. Meanwhile, the combination strategy decreased cardiotoxicity, which is the most serious side effect of DOX. RNA sequencing was performed to explore the precise molecular alterations involved in the combination group. Among the numerous differentially expressed genes, downregulated FHL-2 and upregulated cleaved SPTAN1 were validated in both mRNA and protein levels of HT-29 and SW620 cells. These two proteins might play a pivotal role involving in OMT + DOX synergistic activity. Overall, OMT in combination with DOX presented an outstanding synergistic antitumor effect, indicating that this beneficial combination may offer a potential therapy for CRC patients.
Highlights
Colorectal cancer (CRC) is the third most common malignancy worldwide (Burnett-Hartman et al, 2021)
The results showed that co-treatment with OMT and DOX caused greater apoptosis than exposure to either OMT or DOX alone in both HT-29 and SW620 cell lines (Figures 3B,D)
cancer cell (CRC) is a major gastrointestinal carcinoma that affected approximately 1.8 million people worldwide in 2018 (Liu et al, 2019). Traditional treatments such as surgery, radiation therapy, and chemotherapy are associated with multiple side effects, and the outcomes of CRC therapies are far from satisfactory (Liu et al, 2019)
Summary
Colorectal cancer (CRC) is the third most common malignancy worldwide (Burnett-Hartman et al, 2021). A combination strategy is commonly used in CRC drug therapy (Chapelle et al, 2020). A notable incidence of cardiovascular side effects including tachycardia, hypotension, arrhythmias, and sequentially induced heart toxicity are frequently observed when used clinically (Liu et al, 2020; Galán-Arriola et al, 2021). Combination with other active drugs, especially natural products which possesses low toxicity characteristics, has become a promising strategy to alleviate DOX cardiotoxicity. Oxymatrine (OMT) (Figure 1), one of the primary alkaloids extracted from Sophora flavescens, has been broadly reported to be an active anticancer component in multiple types of malignancies, such as breast cancer, hepatocellular carcinoma (HCC), and non–small-cell lung cancer (NSCLC) (Halim et al, 2019; Lan et al, 2020). The combination of OMT and 5-Fu improved the anticancer effect on HCC cells (Liu et al, 2016a)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
