Artesunate Holistic Treatment In Cancer – Part 3
Artesunate calms the cytokine storm.
Cytokine storm is the main underlying contributor to the morbidity and mortality associated COVID19 pneumonia   . I highlighted the evidence of this reality in a previous 3 part blog post series on the topic of cytokine storm. A March 2020 retrospective study, out of China, found laboratory evidence of cytokine storm in almost all 21 patients with severe or moderate cases of COVID19 . The authors pointed to the cytokine storm for responsibility in the immunogenic damage found. Another recent study of 150 patients out of Wuhan, China, found that those who died from COVID19 had significantly higher IL-6 levels than those who were later discharged from the hospital . Remember, the elevation of the cytokine IL-6 points to cytokine storm. In fact, the authors of the study said:
In a previous blog post, I reviewed how the scientific evidence points to the involvement of cytokine storm in cancer growth and metastatic spread. Even chemotherapy   and radiation  have been shown to trigger cytokine storm leading to the metastatic spread of cancer through various mechanisms. Even the current immunologic saviors (insert sarcasm) check-point inhibitor therapies of today can induce cytokine storm . This point is not conjecture or theory; instead, some of the exact mechanisms of how this can happen is well published . Quieting the cytokine storm is an essential strategy and mechanism to target the fight against the COVID19 virus. This post is not to revisit the connection between cytokine storm and COVID19 or cancer, but to provide wholistic cancer treatment solutions for cancer through the targeting of the cytokine storm.
The answer to cancer is prevention—never get it. Quickly and easily said, but according to current statistics today, that is very hard to do. According to the Prospective Urban Rural Epidemiology (PURE) study of 21 upper, middle, and low- income countries, cancer is now the #1 cause of mortality in upper-income countries . However, even in the most prepared and best of circumstances, bad things happen. If cancer does occur, the answer to cancer can be found in the immune system. The inherent ability of the body to heal from cancer can be found within the immune system. Simply stated, the immune system’s job is to eliminate the body from enemies, both foreign (bacteria, virus, parasites) and domestic (cancer). This evidence is seen in the precision, surgical targeting, and multiple disruptions in the immune system by cancer. Not to give cancer a conscious awareness, but it is clear that cancer sees the immune system as a direct threat to its survival and the success of its ability to grow and spread. In the presence of cancer-mediated immune dysfunction, therapies that identify, target, and modulate the immune system are required to restore optimal immune balance and function against cancer to help eliminate cancer and keep cancer gone.
Enter the wholistic, integrative cancer treatment artesunate. Artemisinin, artesunate, and other derivatives have diverse and specific anti-cancer effects through modifications of the immune system. Some of the specific anti-cancer immune effects include inhibition of:
- Prostaglandin E expression 
- Inhibition of Foxp3 expression in T-cells 
- Decrease in the immunosuppressive signals of IL-10 levels, TGF-beta levels, and Treg cells 
- Inhibition of TNF-alpha production from activated neutrophils, which is a mechanism by which cancer cells protect itself against the immune system  
- Inhibition of tumor-associated macrophage infiltration to the tumor microenvironment, which plays a role in the M2 macrophage polarization to favor cancer growth and metastasis 
- Inhibition of secretion of macrophage-derived pro-inflammatory cytokines, particularly TNF-α and IL-6  
All the points above highlight the knowledge of the detail in how artemisinin, artesunate, and other derivatives help the immune system fight cancer.
Artesunate targets and stimulates the innate immune system. The innate immune system is a key component of the anti-cancer response of the immune system responsible for the hand-to-hand combat needed against cancer. The innate immune system makes use of CD8 cytotoxic T lymphocytes, Natural Killer (NK cells), and many other cells to provide this direct anti-cancer assault. Think of CD8 and NK cells as your own personal army and marines units. As a result of the critical role that the innate immune system plays in anti-cancer defense, suppression of the innate immune system is a widespread finding in cancer and is necessary for cancer to survive, thrive, and drive metastasis. Again, it is almost as if cancer knows its most significant threat and moves to take it out. A large and growing body of evidence points to artesunate, artemisinin and other derivatives in the stimulation of the innate immune system to include:
- Increase in NK cell maturation 
- Increase in NK cell activation 
- Increase in tight binding between NK cells and targeted cancer cells 
- Increase in NK cell degranulation, which is how NK cells can destroy the targeted cancer cells 19
- Increase in the direct, anti-cancer Natural Killer cell (NK cell) cytotoxic activity of cancer cells in a dose-dependent manner 19 21 
- Increase tumor cell sensitivity to NK cell killing activity 22
This evidence links artesunate, artemisinin and other derivatives to an increase in anti-cancer potential and activity through its effects on NK cells.
Another way that artesunate and other artemisinins modulate the immune system against cancer is called Toll-Like Receptors (TLR). Toll-like receptors are part of the pattern recognition receptors (PRR) that respond to pathogen-associated molecular patterns (PAMPs) as a part of the preserved antigen presentation process in the immune response to viral, bacteria, parasitic, and fungi infections  . Quite the mouth full. The short is that TLRs are critical preserved receptors within the immune system to respond to foreign invaders.
Currently, there are ten known Toll-like Receptors. I will focus mainly on TLR-4. This TLR-4 receptor triggers the preserved, immune response to foreign pathogens. For example, TLR-4 is the mechanism through which the endotoxin, Lipopolysaccharide (LPS), from gram-negative bacteria trigger systemic inflammation, including cytokine storm. But what is the connection between TLR-4 and cancer? It is through TLR-4 that the means for metastasis, in part, appears to be initiated . Toll-Like Receptor-4 systemic inflammation is also triggered by virus’ and endogenous molecules produced in the body as a result of tissue injury and necrosis. Take chemotherapy, for example. Excessive damage from high-dose chemotherapy triggers TLR-4 mediated inflammation that has been shown in research to cause cytokine storm  . It is this same cytokine storm that has been shown to cause cancer metastasis. Did I hear a mic drop?
This chemotherapy TLR immune interaction is quite complicated, though. Some studies show that the stimulation of TLR-4 receptors by chemotherapy can simultaneously kill cancer cells and promote their survival at the same time . This apparent complexity likely has more to do with the local death of the primary tumor cells and the simultaneous spread and survival of metastatic cancer cells. Confusing, I know. Maybe, the dose of the chemotherapy has something to do with all this—more on that in an upcoming blog post series on low-dose chemotherapy.
The stimulation of TLR-4 stimulation by high-dose or maximum tolerated chemotherapy has been shown to contribute to cancer growth and an increase in the metastatic spread of cancer. To be clear, maximum tolerated is reference to maximum toxicity that the body can handle. It is the maximum tolerated chemotherapy that is triggering the preserved immune system antigen presentation receptor, TLR-4, to directly stimulate and trigger metastasis. What about “first do no harm”? Into this mechanism steps artesunate. Artesunate has been shown to inhibit this TLR-4 triggered immune response via:
- Inhibition of Toll-like Receptor (particularly TLR-4 and TLR-9) transcription  
- Inhibition of Lipopolysaccharide-TLR-4 mediated cytokine release 17
- Blockade of Lipopolysaccharide mediated TNF-alpha release 
- Inhibition of Lipopolysaccharide mediated IL-6 release (IL-6 is a pro-inflammatory cytokine (immune signal) that, when elevated, is a part of the diagnostic criteria for cytokine storm) 
Oh, but there is more! Artemisinin, artesunate, and other derivatives inhibit NF-kappaB activation . NF-kappaB is a key genetic transcription factor in the production of systemic inflammation. Think of NF-kappaB stimulated systemic inflammation as the bed in which cancer lies.
Can artesunate calm the storm?
What I have just reviewed and described above is the cytokine storm. Cytokine storm can be the result of infectious (virus, bacteria, and fungus) and non-infectious (Tumor Lysis Syndrome, chemotherapy, radiation, and even surgery) causes, as previously discussed. Studies have shown that artemisinin and artesunate, through immunomodulation, can counter cytokine storm from malaria, bacteria infection, viral infection, even sepsis . Now, the evidence points to the truth of the activity of artesunate in the reduction of the steps of cytokine storm in cancer and cancer treatment through immune system modification—called immunomodulation. It is one thing to modulate the immune system. It is quite another to be able to counter the force of cytokine storm. Whatever the cause, artesunate can help to calm the storm—the cytokine storm that is.
 Petric D. Cytokine storm in COVID-19. 2020;10.13140/RG.2.2.27381.73447
 Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19. J Infect. 2020;80(6):607-613. doi:10.1016/j.jinf.2020.03.037
 Ragab D, Eldin HS, Taeimah M, Khattab R, Salem R. The COVID-19 Cytokine Storm; What We Know So Far. Front Immunol. June 2020; https://doi.org/10.3389/fimmu.2020.01446
 Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-2629. doi:10.1172/JCI137244
 Ruan Q, Yang K, Wang W. et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. Mar 2020;46:846–848. https://doi.org/10.1007/s00134-020-05991-x
 Karagiannis GS, Pastoriza JM, Wang Y, et al. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. 2017 Jul 19;9(399):]. Sci Transl Med. 2017;9(397):eaan0026. doi:10.1126/scitranslmed.aan0026
 Gartung A, Yang J, Sukhatme VP, et al. Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor. Proc Natl Acad Sci U S A. 2019;116(5):1698-1703. doi:10.1073/pnas.1803999116
 Blyth B, Cole AJ, Macmanus MP, Martin OA. Radiation therapy-induced metastasis: radiobiology and clinical implications. Clinical and Experimental Metastasis. Nov 2017;35(506). doi: 10.1007/s10585-017-9867-5
 Rotz SJ. Leino D, Szabo S, Mangino JL. Severe cytokine release syndrome in a patient receiving PD-1-directed therapy. Pediatric Blood and Cancer. May 2017;64(12). doi: 10.1002/pbc.26642
 Chang J, Bhasin SS, Bielenberg DR, et al. Chemotherapy-generated cell debris stimulates colon carcinoma tumor growth via osteopontin. FASEB J. 2019;33(1):114-125. doi:10.1096/fj.201800019RR
 Dagenais GR, Leong DP, Rangarajan S, et al. Variations in common diseases, hospital admissions, and deaths in middle-aged adults in 21 countries from five continents (PURE): a prospective cohort study [published correction appears in Lancet. 2020 Mar 7;395(10226):784]. Lancet. 2020;395(10226):785-794. doi:10.1016/S0140-6736(19)32007-0
 Zuo W, Wang ZZ, Xue J. Artesunate induces apoptosis of bladder cancer cells by miR-16 regulation of COX-2 expression. Int J Mol Sci. Aug 2014;15(8):14298-14312. doi:10.3390/ijms150814298
 Zhang LX, Liu ZN, Ye J, et al. Artesunate exerts an anti-immunosuppressive effect on cervical cancer by inhibiting PGE2 production and Foxp3 expression. Cell Biol Int. 2014;38(5):639-646. doi:10.1002/cbin.10244
 Cui C, Feng H, Shi X, et al. Artesunate down-regulates immunosuppression from colorectal cancer Colon26 and RKO cells in vitro by decreasing transforming growth factor β1 and interleukin-10. Int Immunopharmacol. 2015;27(1):110-121. doi:10.1016/j.intimp.2015.05.004
 Jiang W, Li B, Zheng X, et al. Artesunate in combination with oxacillin protect sepsis model mice challenged with lethal live methicillin-resistant Staphylococcus aureus (MRSA) via its inhibition on proinflammatory cytokines release and enhancement on antibacterial activity of oxacillin. Int Immunopharmacol. 2011;11(8):1065-1073. doi:10.1016/j.intimp.2011.02.028
 Hunt S, Yoshida M, Davis CE, Greenhill NS, Davis PF. An extract of the medicinal plant Artemisia annua modulates production of inflammatory markers in activated neutrophils. J Inflamm Res. 2015;8:9-14. Published 2015 Jan 14. doi:10.2147/JIR.S75484
 Wu B., Hu K., Li S., Zhu J., Gu L., Shen H., Hambly B.D., Bao S., Di W. Dihydroartiminisin inhibits the growth and metastasis of epithelial ovarian cancer. Oncol. Rep. 2012;27:101–108.
 Kuang M, Cen Y, Qin R, Shang S. Artesunate Attenuates Pro-Inflammatory Cytokine Release from Macrophages by Inhibiting TLR4-Mediated Autophagic Activation via the TRAF6-Beclin1-PI3KC3 Pathway. Cellular Physiology and Biochemistry. May 2018;47(2):475-488.
 Shakir L, Hussain M, Javeed A, Ashraf M, Riaz A. Artemisinins and Immune System. European Journal of Pharmacology. 2011;668:6-14.
 Wu, R., Wang, L., Kuo, H.D. et al. An Update on Current Therapeutic Drugs Treating COVID-19. Curr Pharmacol. 2020;6:56–70. https://doi.org/10.1007/s40495-020-00216-7
 Houh YK, Kim KE, Park S, et al. The Effects of Artemisinin on the Cytolytic Activity of Natural Killer (NK) Cells. Int J Mol Sci. 2017;18(7):1600. Published 2017 Jul 24. doi:10.3390/ijms18071600
 Stebbins C.C., Watzl C., Billadeau D.D., Leibson P.J., Burshtyn D.N., Long E.O. Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity. Mol. Cell Biol. 2003;23:6291–6299. doi: 10.1128/MCB.23.17.6291-6299.2003.
 Lu Z, Bi J, Wan X. Artemisinin sensitizes tumor cells to NK cell-mediated cytolysis. Research Communications. Apr 2020;524(2):418-423. https://doi.org/10.1016/j.bbrc.2020.01.094
 Hopkins PA, Sriskandan S. Mammalian Toll-like receptors: to immunity and beyond. Clin Exp Immunol. 2005;140(3):395-407. doi:10.1111/j.1365-2249.2005.02801.x
 Maru Y. Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation. Cell Mol Immunol. 2010;7(2):94-99. doi:10.1038/cmi.2009.113
 Ran S. The Role of TLR4 in Chemotherapy-Driven Metastasis. Cancer Res. 2015;75(12):2405-2410. doi:10.1158/0008-5472.CAN-14-3525
 Volk-Draper L, Hall K, Griggs C, et al. Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner. Cancer Res. 2014;74(19):5421-5434. doi:10.1158/0008-5472.CAN-14-0067
 Oblak A, Jerala R. Toll-like receptor 4 activation in cancer progression and therapy. Clin Dev Immunol. 2011;2011:609579. doi:10.1155/2011/609579
 Li B, Zhang R, Li J, et al. Antimalarial artesunate protects sepsis model mice against heat-killed Escherichia coli challenge by decreasing TLR4, TLR9 mRNA expressions and transcription factor NF-kappa B activation. Int Immunopharmacol. 2008;8(3):379-389.
 Wan RJ and Wan RJ. Effects of Artesunate prevent nephritis via the Toll‑like receptor 4/nuclear factor‑κB signaling pathway in rats. Mol Med Rep. 2071;16:6389-6395.
 Zhu C, Xiong Z, Chen X, et al. Artemisinin attenuates lipopolysaccharide-stimulated proinflammatory responses by inhibiting NF-κB pathway in microglia cells. PLoS One. 2012;7(4):e35125. doi:10.1371/journal.pone.0035125
 Li B, Zhang R, Li J, Zhang L, Ding G, Luo P, He S, Dong Y, Jiang W, Lu Y, Cao H, Zheng J, Zhou H: Antimalarial artesunate protects sepsis model mice against heat-killed Escherichia coli challenge by decreasing TLR4, TLR9 mRNA expressions and transcription factor NF-kappa B activation. Int Immunopharmacol 2008; 8: 379-389.
 Wang SJ, Gao Y, Chen H, et al. Dihydroartemisinin inactivates NF-κB and potentiates the anti-tumor effect of gemcitabine on pancreatic cancer both In vitro and In vivo. Cancer Letters. 2010;293(1):99–108.
 Yao W, Wang F, Wang H. Immunomodulation of artemisinin and its derivatives. Science Bulletin. Sept 2016;61(18):1399-1406. https://doi.org/10.1007/s11434-016-1105-z
An Oasis of Healing is an integrative medical and healing facility utilizing alternative cancer treatments that help patients and their families learn to re-establish health after having been diagnosed with cancer.
By incorporating alternative and conventional medical services, natural healing modalities, high-quality nutritional products, and a unique educational and training program, we inspire patients to regain their birthright – health.