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Garden Herbs and Cancer Treatment: A pharmacology based framework allows for the identification of novel cancer immunotherapeutic agents derived from Traditional Chinese Medicinal herbs.
As the leading cause of death worldwide, cancer poses a significant global health crisis (Bray et al. 2018). In the past decade, the breakthrough of immunotherapy as a cancer treatment has transformed our strategies to combat tumors. Cancer immunotherapy exploits the host’s immune system to treat cancer through various mechanisms of action (Farkona et al. 2016). The considerable success of immunotherapeutic agents in clinical responses to multiple types of cancer has contributed to rapid growth of the field in recent years, triggering a new era in cancer treatment (Farkona et al. 2016).
Cancer immunotherapy employs a multifaceted treatment approach that combines immune enhancement with immune normalization (Cai et al. 2021). Immune enhancement involves harnessing an anti-tumor immune response by the host, while immune normalization involves the identification of defects in the host immune response and the development of strategies to confront these deficiencies (Sanmamed and Chen 2018). Although breakthroughs in immunotherapy have revolutionized cancer treatment, the current response rate to cancer immunotherapy in patients is only 20% (Velcheti et al. 2016). Therefore, one of the main priorities in current cancer research is to uncover novel immunotherapeutic agents to increase its effectiveness as a treatment approach.
Traditional Chinese Medicine (TCM) has been practiced for thousands of years and is widely used as an alternative treatment for cancer (Xiang et al. 2019). Numerous natural products derived from Chinese herbs possess regulatory effects on tumor microenvironments (Cai et al. 2021). Cai et al. took advantage of the potential use of Chinese herb-derived compounds as novel and effective cancer treatments by constructing a systems pharmacological-based approach for identifying novel immunotherapeutic agents. This goal of this investigative study was to find new compounds that could potentially be used as ingredients for cancer immunotherapy.
Systems pharmacology is based on the principles of systems biology, an approach which uses modeling and quantitative analysis to understand the larger picture of a complex biological system by putting its pieces together (Wanjek 2011). Systems pharmacology expands upon this by looking at how drugs affect the human body as a single complex biological system (Wanjek 2011). In order to investigate potential immunotherapeutic agents derived from Chinese herbs, the researchers developed a five step systems pharmacology-based framework.
First, the researchers investigated 525 traditional Chinese herbs through literature mining in order to discover cancer-related herbs. Literature mining helped to narrow the scope of the study by highlighting the herbs most highly related to cancer. Of the 525 herbs investigated, 66 demonstrated significant associations with cancer (Cai et al. 2021).
Next, the researchers obtained the chemical compounds and corresponding targets of the 66 cancer-related herbs from databases to construct an herb-compound-target (HCT) network. The researchers compared this HCT network with a set of genes related to cancer immune response (CIR) to narrow down potential immunotherapeutic natural products. This HCT analysis allowed the researchers to identify the herbs, targets, and compounds with the highest degrees of compound-protein interactions, which is indicative of important influences in cancer immunotherapy (Cai et al. 2021).
To elucidate the molecular mechanisms underlying the cancer immunotherapeutic effects of the natural products, the researchers performed an enrichment analysis to see which biological pathways and processes were significantly associated with CIR genes. Enrichment analysis suggested that CIR genes may modulate cell growth and death. The researchers then performed a second enrichment analysis looking specifically at immune system processes. They found that most of the pathways they examined were associated with both immune response activation and immune normalization. Specifically, they found that these anti-cancer herbs play an important role in preventing tumor immune escape, which is a key mechanism of cancer progression that allows tumors to escape immune surveillance (Seliger 2005).
To narrow down potential cancer immunotherapeutic agent candidates, the researchers integrated the HCT network of 66 cancer-related herbs with 5 sets of CIR-related genes. 49 of these natural products demonstrated correlations with cancer immunotherapy in all 5 models.
One of these potential candidates was the herb huangqin (Scutellaria baicalensis), which possessed the highest number of potential cancer immunotherapy agents of all of the 66 herbs tested. The researchers aimed to elucidate the anti-cancer mechanism of action employed by huangqin. To do this, they created a compound-target network for the herb, which allowed them to find its three primary ingredients: baicalin, wogonin, and oroxylin A. These novel agents demonstrate promising potential for use in cancer immunotherapy and illuminate the experimental value of a systems pharmacology-based approach for identifying the anti-cancer potential of natural products.
This experiment demonstrates the value of a systems biology approach to biomedical research. Mapping out all of the herbs, their compounds, and their molecular targets and analyzing their interactions with CIR-related genes provided an effective method for identifying potential immunotherapeutic agents. However, while the results of this study demonstrate the enormous potential of a systems biology framework for discovering new anti-cancer products, there are several crucial limitations of this study. First off, although the researchers integrated a large amount of data on compound-target interactions, Chinese herbs, and CIR-related genes, the incompleteness of this work may be inevitable. Further studies conducted in a similar fashion are fundamental for unlocking novel immunotherapeutic agent candidates. Secondly, the connections found between specific molecular compounds and cancer immune response genes in quantitative analyses may not always translate to the in vivo (in a living cell) relationship in all cases. Therefore, it is essential to combine large in vitro systems based analyses with in vivo validation studies in order to confirm a particular candidate as an immunotherapeutic agent.
This study accentuates scientific methods which are pioneering cancer treatment. It turns out that the garden herbs planted in our backyard could be used to treat cancer through immunotherapy!
Kade McCulloch is a Sophomore Biology Major and Public Health Minor at Davidson College. Contact him at kamcculloch@davidson.edu!
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RESOURCES
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A., et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, American Cancer Society, 2018; 68: 394-424.
Cai, C., Wu, Q., Hong, H., He, L., Liu, Z., Gu, Y., et al. In silico identification of natural products from Traditional Chinese Medicine for cancer immunotherapy, Sci Rep, 2021; 11: 3332.
Farkona, S., Diamandas, E.P., and Blasutig, I.M. Cancer immunotherapy: the beginning of the end of cancer? BMC Med, 2016; 14: 73.
Sanmamed, M.F., and Chen L. A paradigm shift in cancer immunotherapy: From enhancement to normalization, Cell, 2018; 175(2): 313-326.
Seliger, B. Strategies of tumor immune evasion, BioDrugs, 2005; 19(6): 347-354.
Wanjek, C. Systems biology as defined by NIH: An intellectual resource for integrative biology, NIH Catalyst, 2011; 19: 6.
Xiang, Y., Guo, Z., Zhu, P., Chen, J., and Huang Y. Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science, Cancer Med, 2019; 8(5): 1958-1975.
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