Abstract
The high morbidity and mortality associated with colorectal cancer (CRC) are largely due to the invariable development of chemoresistance to classic chemotherapies, as well as intolerance to their significant toxicity. Many pharmaceutical formulations screened from natural plant extracts offer safe, inexpensive, and multi-target therapeutic options. In this study, we demonstrated that Berberis vulgaris L. (Berberine) and Andrographis paniculata (Burm. f.) Nees (Andrographis) extracts exerted their synergistic amplified anti-cancer effects by jointly inhibiting cell viability, suppressing colony formation, and inducing cell cycle arrest. Consistent with our in-vitro findings, the amplified synergistic anti-cancer effects were also observed in subcutaneous xenograft preclinical animal models, as well as patient-derived primary tumor organoids. To explore the molecular mechanisms underlying the amplified synergistic anti-cancer effects, RNA sequencing was performed to identify candidate pathways and genes. A transcriptome analysis revealed that DNA-replication-related genes, including FEN1, MCM7, PRIM1, MCM5, POLA1, MCM4, and PCNA, may be responsible for the enhanced anticancer effects of these two natural extracts. Taken together, our data revealed the powerful enhanced synergistic anti-CRC effects of berberine and Andrographis and provide evidence for the combinational targeting of DNA-replication-related genes as a promising new strategy for the therapeutic option in the management of CRC patients.
Highlights
Colorectal cancer (CRC) ranks as the third most common malignancy worldwide and remains one of the leading causes of cancer-related deaths globally [1]
MCM7, PRIM1, MCM5, POLA1, MCM4, and Interestingly, treatment for several decades and is often the sole method to treat the cases of early diagamong these proteins, observed the significantly enhanced downregulation of nosis but is no longer we effective in the majority of the advanced cases where cancer has
PRIM1 protein expression in cells treated by the berberine and Androalready metastasized [7]
Summary
Colorectal cancer (CRC) ranks as the third most common malignancy worldwide and remains one of the leading causes of cancer-related deaths globally [1]. In 2021, an estimated 149,500 adults in the United States will be diagnosed with CRC, and approximately 53,000 will succumb to CRC-related deaths [2]. The survival benefits of patients with early-stage CRC have increased significantly over the past few decades, primarily due to the advances in early detection and the increased uptake of screening [3,4]. Given the higher disease incidence and diagnosis of cancer at advanced stages, chemotherapy, rather than surgery, has become the standard approach for the management of such patients [8]. The therapeutic benefit of chemotherapy has been limited due to the Pharmaceuticals 2022, 15, 262.
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