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ANDROGRAPHIS RESEARCH

1. A combined treatment with berberine and andrographis exhibits enhanced anti-cancer activity through suppression of DNA replication in colorectal cancer. 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. [Zhao Y, Roy S, Want C, Goel A. A combined treatment with berberine and andrographis exhibits enhanced anti-cancer activity through suppression of DNA replication in colorectal cancer. Pharmaceuticals.2022;15:262.]

2. A combined treatment with melatonin and andrographis promotes autophagy and anti-cancer activity in colorectal cancer. Colorectal cancer (CRC) is one of the most frequent malignancies worldwide and remains one of the leading causes of cancer-related deaths in the United States. The high degree of morbidity and mortality associated with this disease is largely due to the inadequate efficacy of current treatments as well the development of chemoresistance. In recent years, several pharmaceutical agents screened from natural products have shown the promise to offer a safe, inexpensive, and synergistically multi-targeted treatment option in various cancer. Given the growing evidence of anti-carcinogenic properties of two natural compounds, melatonin (MLT) and andrographis (Andro), we aimed to evaluate their synergistic anti-cancer effects in CRC. We demonstrate that indeed these two compounds possessed a synergistic anti-cancer effect in terms of their ability to inhibit cell viability, suppression of colony-formation and induction of apoptosis (p<0.05). In line with our in-vitro findings, we were able to validate this combinatorial anti-cancer activity in xenograft animal models (p<0.001) as well as tumor-derived 3D organoids (p<0.01). RNA-sequencing analysis revealed candidate pathways and genes that mediated anti-tumor efficacy of MLT and Andro in CRC, among which autophagy pathway and related genes, including NR4A1, CTSL and Atg12, were found to be primarily responsible for the increased anti-cancer effect by the two natural products. In conclusion, our data reveal a potent and synergistic therapeutic effect of MLT and Andro in the treatment of CRC and provides a rationale for suppressing autophagy February 22, 2022 in cancer cells as a potential therapeutic strategy for CRC. [Zhao Y, Wang C, Goel A. A combined treatment with melatonin and andrographis promotes autophagy and anti-cancer activity in colorectal cancer. Carcinogenesis. 2022; January. Published online ahead of print.]

3. Andrographis-mediated chemosensitization through activation of ferroptosis and suppression of β-catenin/Wnt-signaling pathways in colorectal cancer. Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality in the USA. As much as 50–60% of CRC patients develop resistance to 5-fluorouracil (5FU)-based chemotherapeutic regimens, attributing the increased overall morbidity and mortality. In view of the growing evidence that active principles in various naturally occurring botanicals can facilitate chemosensitization in cancer cells, herein, we undertook a comprehensive effort in interrogating the activity of one such botanical—andrographis—by analyzing its activity in CRC cell lines [both sensitive and 5FU resistant (5FUR)], a xenograft animal model and patient-derived tumor organoids. We observed that combined treatment with andrographis was synergistic and resulted in a significant and dose-dependent increase in the efficacy of 5FU in HCT116 and SW480 5FUR cells (P < 0.05), reduced clonogenic formation (P < 0.01) and increased rates of caspase9-mediated apoptosis (P < 0.05). The genomewide expression analysis in cell lines led us to uncover that activation of ferroptosis and suppression of β-catenin/Wnt-signaling pathways were the key mediators for the anti-cancer and chemosensitizing effects of andrographis. Subsequently, we validated our findings in a xenograft animal model, as well as two independent CRC patient-derived organoids—which confirmed that combined treatment with Andrographis was significantly more effective than 5FU and andrographis alone and that these effects were in part orchestrated through dysregulated expression of key genes (including HMOX1, GCLC, GCLM and TCF7L2) within the ferroptosis and Wnt-signaling pathways. Collectively, our data highlight that andrographis might offer a safe and inexpensive adjunctive therapeutic option in the management of CRC patients. [Sharma P, Shimura T, Banwait JK, Goel A. Andrographismediated chemosensitization through activation of ferroptosis and suppression of β-catenin/Wntsignaling pathways in colorectal cancer. Carcinogenesis. 2020:1-10.]

4. Andrographis overcomes 5-fluorouracil associated chemoresistance through inhibition of DKK1 in colorectal cancer. Colorectal cancer (CRC) ranks as the third leading cause of cancer-related deaths in the US. 5- fluorouracil (5FU)-based chemotherapeutic drug remains a mainstay of CRC treatment. Unfortunately, ~50-60% of patients eventually develop resistance to 5FU, leading to poor survival outcomes. Our previous work revealed that andrographis enhanced 5FU-induced anti-cancer activity, but the underlying mechanistic understanding largely remains unclear. In this study, we first established 5FU resistant (5FUR) CRC cells and observed that combined treatment with andrographis-5FU in 5FUR cells exhibited superior effect on cell viability, proliferation and colony formation capacity compared to individual treatments (p<0.001). To identify key genes and pathways responsible for 5FU resistance, we analyzed genome-wide transcriptomic profiling data from CRC patients who either responded or did not respond to 5FU. Among a panel of differentially expressed genes, DKK1 overexpression was a critical event for 5FU resistance. Moreover, andrographis significantly downregulated 5FU-induced DKK1 February 22, 2022 overexpression, accompanied with enhanced anti-tumor effects by abrogating downstream Akt-phosphorylation. In line with in vitro findings, andrographis enhanced 5FU-induced anti-cancer activity in mice xenografts and patient-derived tumoroids (p<0.01). In conclusion, our data provide novel evidence for andrographis-mediated reversal of 5FU resistance, highlighting its potential role as an adjunct to conventional chemotherapy in CRC. [Zhao Y, Wang C, Goel A. Andrographis overcomes 5-fluorouracil associated chemoresistance through inhibition of DKK1 in colorectal cancer. Carcinogenesis. 2021. Advanced publication data: https://doi.org/10.1093/carcin/bgab027]

5. Enhanced anti-cancer activity of andrographis with oligomeric proanthocyanidins through activation of metabolic and ferroptosis pathways in colorectal cancer. 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 ofer 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 profling identifed 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. [Shimura T, Sharma P, Sharma GG, Banwait JK, Goel A. Enhanced anti-cancer activity of andrographis with oligomeric proanthocyanidins through activation of metabolic and ferroptosis pathways in colorectal cancer. Sci Rep. 2021;11(1):7548.]

6. Antitumor effects of Andrographis via ferroptosis-associated genes in gastric cancer. The overall prognosis of advanced/metastatic gastric cancer (GC) remains poor despite the development of pharmacotherapy. Therefore, other treatment options, such as complementary and alternative medicine, should be considered to overcome this aggressive malignancy. Andrographis, which is a generally unharmful botanical compound, has gained increasing interest for its anticancer effects in multiple malignancies via the regulation of cancer progression-associated signaling pathways. In the present study, a series of in vitro experiments (cell proliferation, colony formation and apoptosis assays) was designed to elucidate the antitumor potential and mechanism of Andrographis in GC cells. The present study demonstrated that Andrographis exerted antitumor effects in GC cell lines (MKN74 and NUGC4) by inhibiting proliferation, reducing colony formation and enhancing apoptotic activity. Furthermore, it was demonstrated that the expression levels of the ferroptosis-associated genes heme oxygenase-1, glutamate-cysteine ligase catalytic and glutamate-cysteine ligase modifier were significantly upregulated after Andrographis treatment in both GC cell lines in reverse transcription- February 22, 2022 quantitative PCR experiments (P<0.05); this finding was further confirmed by immunoblotting assays (P<0.05). In conclusion, to the best of our knowledge, the present study was the first to demonstrate that Andrographis possessed antitumor properties by altering the expression levels of ferroptosis-associated genes, thereby providing novel insights into the potential of Andrographis as an adjunctive treatment option for patients with metastatic GC. [Ma R, Shimura T, Yin C, et al. Antitumor effects of andrographis via ferroptosis-associated genes in gastric cancer. Oncol Lett. 2021;22(1):523.

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