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Suppression of colorectal cancer cell growth by combined treatment of 6-gingerol and γ-tocotrienol via alteration of multiple signalling pathways

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Abstract

Our previous study reported that combined treatment of γ-tocotrienol with 6-gingerol showed promising anticancer effects by synergistically inhibiting proliferation of human colorectal cancer cell lines. This study aimed to identify and elucidate molecular mechanisms involved in the suppression of SW837 colorectal cancer cells modulated by combined treatment of γ-tocotrienol and 6-gingerol. Total RNA from both untreated and treated cells was prepared for transcriptome analysis using RNA sequencing techniques. We performed high-throughput sequencing at approximately 30–60 million coverage on both untreated and 6G + γT3-treated cells. The results showed that cancer-specific differential gene expression occurred and functional enrichment pathway analysis suggested that more than one pathway was modulated in 6G + γT3-treated cells. Combined treatment with 6G + γT3 augmented its chemotherapeutic effect by interfering with the cell cycle process, downregulating the Wnt signalling pathway and inducing apoptosis mainly through caspase-independent programmed cell death through mitochondrial dysfunction, activation of ER-UPR, disruption of DNA repair mechanisms and inactivation of the cell cycle process through the downregulation of main genes in proliferation such as FOXM1 and its downstream genes. The combined treatment exerted its cytotoxic effect through upregulation of genes in stress response activation and cytostatic effects demonstrated by downregulation of main regulator genes in the cell cycle. Selected genes involved in particular pathways including ATF6, DDIT3, GADD34, FOXM1, CDK1 and p21 displayed concordant patterns of gene expression between RNA sequencing and RT-qPCR. This study provides new insights into combined treatment with bioactive compounds not only in terms of its pleiotropic effects that enhance multiple pathways but also specific target genes that could be exploited for therapeutic purposes, especially in suppressing cancer cell growth.

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Acknowledgements

The research grant was supported by the Higher Institutions Centre of Excellence (HICoE; grant no: 106-64-01-005) from Ministry of Higher Education and The National University of Malaysia (UKM).

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Authors and Affiliations

  1. UKM Medical Molecular Biology Institute (UMBI), UKM Medical Center, Jalan Ya’acob Latiff, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia

    Khairunnisa’ Md Yusof & Rahman Jamal

  2. Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Ya’acob Latiff, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia

    Suzana Makpol & Wan Zurinah Wan Ngah

  3. BioEasy Sdn. Bhd, Setia Avenue, Setia Alam Seksyen U13, 40170, Shah Alam, Selangor, Malaysia

    Lye Siew Fen

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  1. Khairunnisa’ Md Yusof
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  4. Rahman Jamal
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Yusof, K.M., Makpol, S., Fen, L.S. et al. Suppression of colorectal cancer cell growth by combined treatment of 6-gingerol and γ-tocotrienol via alteration of multiple signalling pathways. J Nat Med 73, 745–760 (2019). https://doi.org/10.1007/s11418-019-01323-6

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