Abstract
Colorectal cancer is the third most frequently diagnosed cancer worldwide. Clinically, chemotherapeutic agents such as FOLFOX are the mainstay of colorectal cancer treatment. However, the side effects including toxicity of FOLFOX stimulated the enthusiasm for developing adjuvants, which exhibit better safety profile. Turmeric extract (TE), which has been previously shown to suppress the growth of human and murine colon xenografts, was further demonstrated here for its inhibitory effects on colon cancer patient-derived xenografts (PDX). PDX models were successfully established from tissues of colon cancer patients and the PDX preserved the heterogeneous architecture through passages. NOD/SCID mice bearing PDX were treated either with TE or FOLFOX and differential responses toward these treatments were observed. The growth of PDX, metastasis and tumor recurrence in PDX-bearing mice were suppressed after TE treatments with 60% anti-tumor response rate and 83.3% anti-metastasis rate. Mechanistic studies showed that TE reduced tumor cell proliferation, induced cell apoptosis, inhibited metastasis via modulating multiple targets, such as molecules involved in Wnt and Src pathways, EMT and EGFR-related pathways. Nevertheless, FOLFOX treatments inhibited the PDX growth with sharp decreases of mice body weight and only mild anti-metastasis activities were observed. Furthermore, in order to have a better understanding of the underlying mechanisms, network pharmacology was utilized to predict potential targets and mechanism. In conclusion, the present study demonstrated for the first time that oral TE treatment was effective to suppress the growth of colon PDX and the recurrence of colon tumors in mice. The findings obtained from this clinically relevant PDX model would certainly provide valuable information for the potential clinical use of TE in colorectal cancer patients. The application of PDX model was well illustrated here as a good platform to verify the efficacy of multi-targeted herbal extracts.
Highlights
Colorectal cancer (CRC) is the third most frequently diagnosed malignancy and is the second leading cause of cancer death worldwide [1]
Quantification of two commercially available chemical markers, curcumin and Arturmerone (Sigma-Aldrich, MO, USA), in turmeric ethanolic extract was performed using by UPLC and the chemical profiles were registered [27]
Standardization of turmeric ethanolic extract used in the present study was same as the method reported previously, in which the 3-D chromatograms of the extract as well as the extracted ion chromatograms (EIC) and MS spectra of the marker compounds were well reported previously [27]
Summary
Colorectal cancer (CRC) is the third most frequently diagnosed malignancy and is the second leading cause of cancer death worldwide [1]. The incidence and death rates of CRC decreased among individuals aged ≥ 50 years, but increased by 13% in those aged less than 50 years [2]. Metastasis results in nearly 90% of all cancer deaths [3] and it occurs in 20%–30% of CRC patients [2, 4]. Poor prognosis of patients with non-resectable stage III–IV metastatic CRC (mCRC) provoked the development of therapeutics with novel mechanisms of action. There remains high unmet needs for safer adjuvant and/or therapeutic agents for mCRC patients, which could be searched from natural sources
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