Abstract
The high degree of morbidity and mortality in colorectal cancer (CRC) patients is largely due to the development of chemoresistance against conventional chemotherapeutic drugs. In view of the accumulating evidence that various dietary botanicals offer a safe, inexpensive and multi-targeted treatment option, herein, we hypothesized that a combination of Andrographis paniculata and Oligomeric Proanthocyanidins (OPCs) might interact together with regard to anti-tumorigenic activity in CRC. As a result, we demonstrated the enhanced anti-cancer activity between these two botanical extracts in terms of their ability to inhibit cancer cell growth, suppress colony formation and induce apoptosis. Furthermore, we validated these findings in subcutaneous xenograft model and in patient derived primary epithelial 3D organoids. Transcriptomic profiling identified involvement of metabolic pathways and ferroptosis-associated genes, including HMOX1, GCLC and GCLM, that may be responsible for the increased anti-tumorigenic activity by the two compounds. Collectively, our study provides novel evidence in support of the combinatorial use of andrographis and OPCs as a potential therapeutic option, perhaps as an adjunctive treatment to classical drugs, in patients with colorectal cancer.
Highlights
Context, a recent study emphasized the need for developing more informed anti-cancer therapeutic regimens that target distinct cancer pathways simultaneously, instead of their sequential administration, which is often inadequate but still exposes the patient to toxicity and expense of these d rugs[6]
While previous studies have interrogated the efficacy of andrographis on specific pathways in cancer cells[21, 22], we for the first time performed a series of systematic cell culture, xenograft model, and patient-derived tumor organoid experiments to evaluate the combined anti-tumorigenic effect of andrographis and oligomeric proanthocyanidins (OPCs), and performed a whole genome transcriptomic profiling to find out key pathways involved in the combined treatment of andrographis and OPCs in colorectal cancer
In order to evaluate whether andrographis has any synergistic activity in enhancing the efficacy of OPCs in Colorectal cancer (CRC) cells as reported previously[15, 17, 20], we investigated the effects of both compounds individually, as well as their combination, in HCT116 and HT29 cell lines
Summary
Context, a recent study emphasized the need for developing more informed anti-cancer therapeutic regimens that target distinct cancer pathways simultaneously, instead of their sequential administration, which is often inadequate but still exposes the patient to toxicity and expense of these d rugs[6]. Given the fact that a most effective anti-cancer treatment approach must be multi-targeted in nature, and because both andrographis and OPCs tend to exhibit their cancer inhibitory activity through distinct pathways, we hypothesized that a combination treatment with these botanical extracts might offer an enhanced antitumorigenic activity in CRC. This hypothesis was further supported by the school of thought that such dietary compounds are generally quite safe and inexpensive—providing a rationale for evaluating their combinatorial efficacy, vis-à-vis their anti-cancer activity individually. While previous studies have interrogated the efficacy of andrographis on specific pathways in cancer cells[21, 22], we for the first time performed a series of systematic cell culture, xenograft model, and patient-derived tumor organoid experiments to evaluate the combined anti-tumorigenic effect of andrographis and OPCs, and performed a whole genome transcriptomic profiling to find out key pathways involved in the combined treatment of andrographis and OPCs in colorectal cancer
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