Artesunate

Story at a glance

Artesunate

The parent compound of artesunate is artemisinin which is the primary active component of the plant sweet wormwood (Artemisia annua L.). Sweet wormwood has been used in Chinese medicine since ancient times to treat fever. The therapeutic potential of artesunate achieved global attention in 2015 when Dr. Youyou was awarded the Nobel Prize in Medicine or Physiology for her discovery of artemisinin’s powerful therapeutic value in treating malaria. Dr. Tu first extracted artemisinin from the sweet wormwood plant in 1972 in her search for Chinese medicinal plants against malaria. Studying ancient textbooks, she discovered the correct preparation method of A. annua at low temperatures instead of frequently used hot decoction to obtain the most effective extract against malaria infections. Although there are around 200 million cases of malaria a year worldwide, the vast majority of these are now curable and will be treated with artemisinin combination therapy. This discovery is another example in the history of medicine of why these traditional healing disciplines, such as traditional Chinese medicine (TCM), Ayurveda, and others have been in existence for at least 5000 years. Today, artemisinin and its derivatives are used worldwide as standard treatment for malaria.

Apart from being used to treat malaria, artesunate has also been found to have biological activity against a variety of CFCs and it has produced some impressive results on people when combined with chemotherapy, as well as when combined with vitamin C. Furthermore, artesunate has advantages over conventional treatments. While being effective in eliminating CFCs directly, artesunate can contribute to healing by strengthening the immune system and improving the quality of life in people. Artesunate treatment has often been used in combination with intravenous high-dose vitamin C, which has revealed their synergistic action and increased survival of people with advanced CFCs.

Artesunate can be administered as an intramuscular injection, orally, rectally, as well as intravenously. When taken orally, it only remains active (half-life) for 20 to 45 minutes, during which time it is metabolized enzymatically via hydrolysis to dihydroartemisinin (DHA), the active metabolite that is responsible for its antimalarial activity and anti-tumor activity in a variety of malignant tumors, yet it is non-toxic to normal, healthy cells. The anticancer effects of DHA include inhibiting proliferation (growth), inducing apoptosis (programmed cell death), inhibiting tumor metastasis, and preventing new blood vessel growth (angiogenesis).  A tumor cannot grow 1 mm without new blood vessels. Artesunate further enhances immune function, induces autophagy, and stresses the endoplasmic reticulum where proteins are produced, fats are metabolized, and calcium is stored. This results in the CFCs becoming extremely vulnerable and weakened.

However, when administered orally, the absorption of artemisinin is not adequate (poor bioavailability) to obtain therapeutic blood levels, and it gets metabolized quickly (short half-life), which further limits its accumulation in the blood and therefore fails to have a significant effect on CFCs. To improve the clinical usefulness additional derivatives such as artesunate, dihydroartemisin, artemether, arteeter, and artemisone were developed. The derivatives of artemisinin are collectively called artemisinins. Artesunate is the most widely used artemisinin derivative today and since it is administered intravenously, adequate blood levels are ensured (100% bioavailability) and since it does not pass through the liver first, as it would if taken orally, half-life (length of time it is active) is greatly extended compared to that of oral artesunate. 

Since the discovery and isolation by Dr. Youyou Tu, the accumulated research on artemisinin and its various derivatives has revealed biological activity that is also able to eliminate CFCs, viruses as well as the protozoa causing malaria, Leishmania, Trypanosoma, Toxoplasma gondii, Neospora caninum, Eimeria tenella, Acanthamoeba castellanii, Naegleria fowleri, Cryptosporidium parvum, Giardia lamblia, and Babesia, which often accompanied the Lyme’s spirochete.

Furthermore, its effectiveness extends to the helminths (worm parasites), including the roundworms (Nematodes), flatworms, i.e., tapeworms, (cestodes), and trematodes like schistosomes as well as the liver flukes Clonorchis sinensis and Opisthorchis viverrini, Paragonimus westermani (lung fluke), and trematodes Heterophyes heterophyes, and Paramphistomum microbothrium), and a few ectoparasites (lives on the skin) monogenea Dactylogyrus and Gyrodactylus.

Artesunate has also been studied for its activity against 55 different CFC lines in the Developmental Therapeutics Program of the National Cancer Institute. It seems to be most effective against leukemia and colon CFCs, whereas the lowest sensitivity was found in non-small cell lung CFCs cell lines. And, it was shown to have intermediate sensitivity when used for melanomas, breast, ovarian, prostate, CNS, and kidney (renal) CFCs. Artesunate has been shown to effectively eliminate multiple CFCs from various origins including colon, breast, leukemia, melanoma, central nervous system, ovarian, renal (kidney), and prostate. Further, the active metabolite of artemisinin, dihydroartemisinin (DHA), is also effective in the treatment of CFCs of the breast, glioma (brain), colon, lung, ovarian, pancreatic, kidney, and leukemia.

Here are all the locations from which CFCs originate, against which artemisinin has been found to be effective:

  1. Bladder 
  2. Breast 
  3. Cervical 
  4. Colorectal 
  5. Esophageal 
  6. Stomach 
  7. Glioblastoma and other primary tumors in the brain
  8. Head and Neck 
  9. Leukemia 
  10. Lung 
  11. Lymphoma 
  12. Melanoma 
  13. Osteosarcoma 
  14. Ovarian 
  15. Pancreatic 
  16. Prostate 
  17. Kidney

Like many other natural products or derivatives, artesunate has multiple targets on CFCs with several mechanisms of action, unlike synthetic drugs, which usually have one specific desired action, and multiple undesired consequences.

Anti-proliferative (Anti-growth)

Uncontrolled growth is a typical trait of CFCs and it is due to the altered regulation of several growth signaling pathways of the cell. Many of these alterations are caused by local signals surrounding the tumor such as inflammatory cytokines, acidity, and low oxygen levels (hypoxia). Artesunate has been shown to efficiently resist the growth of CFCs by altering many of the pathways including inhibiting the PI3K/Akt/mTOR pathway, inhibiting enzyme COX-2 and its production of prostaglandins (particularly PGE-2), inhibiting nitric oxide (NO) production, and decreasing HIF-1 alpha levels. Artesunate additionally stops the CFCs from dividing at specific phases, G2/M and G0/G1 hence they are unable to grow or metastasize.


Pro-apoptotic (Programmed Death of CFCs)

Programmed cell death, called apoptosis, is a key process of the body in regulating the optimal number of cells and eliminating abnormal cells. CFCs often evade this process by silencing multiple signals that normally trigger apoptosis. Artesunate has been found to “re-induce” apoptosis in CFCs by several mechanisms. Some of those are inhibition of STAT3 which is a protein commonly overactive in CFCs that controls antiapoptotic genes such as Bcl-2 and Bcl-xl. Another way in which artemisinin reactivates apoptosis is through the activation of caspase-3, caspase-8, and cascade-9 that signal the cell to die. Moreover, artesunate increases the expression of tumor suppressor genes p21 and p53, which had been silenced by the tumor. The genes p21 and p53 are important regulators of the cell cycle and when they are inactive the CFCs receive no signal to die and so they go on to live immortally.


Triggers Ferroptosis

Ferroptosis, a type of programmed cell death driven by ferritin or iron is induced significantly by artesunate and other artemisinin derivatives. In this regard, it is an oxidative, iron-dependent form of regulated cell death characterized by the accumulation of free radicals (ROS) and lipid peroxidation (breaks down cellular membranes) products that are lethal to cells. Many lines of evidence show that triggering ferroptosis is an effective strategy to kill CFCs, especially aggressive malignancies resistant to chemotherapy. DHA sensitizes CFCs to ferroptosis by increasing the accumulation of iron within the cell by causing lysosomes (waste disposal units) to degrade ferritin and release free iron. The free iron combines with other substances and produces many free radicals that damage and destroy the cell. Ferritin, a protein that stores iron is overexpressed in many CFCs, compared to normal cells. CFCs replicate much faster than normal cells therefore they have a greater need for iron and ferritin. Ultimately, this process inside the CFCs overwhelms the detoxification capacity by requiring it to use its already small amount of antioxidant enzymes, hence the cell dies.


Anti-angiogenesis

To meet the increased demand for nutrients required for growth and gain new routes for spreading and metastasizing, CFCs need to grow a dense network of blood vessels (angiogenesis). A major trigger for angiogenesis is the lack of oxygen (hypoxia) near and within the tumor which activates a transcription factor called hypoxia-inducible factor-1 (HIF-1). Artesunate, like ascorbate (vitamin C), suppresses HIF-1 in CFCs thereby preventing it from initiating new blood vessel growth (angiogenesis). Finally, it inhibits the production of nitric oxide (NO), vascular endothelial growth factor (VEGF), and the vascular endothelial growth factor receptor (VEGFR), all of which are required for angiogenesis. If these factors are not suppressed, CFCs are quite aggressive. Hence artesunate is an essential tool in eliminating CFCs.


Anti-metastatic

90% of mortality from CFCs occurs due to metastasis. Therefore, if metastases can be prevented, CFCs are no longer a serious problem. With conventional treatments such as chemotherapy and radiotherapy, the opposite occurs. Not only do they fail to prevent metastasis but increase the likelihood of metastases by enhancing each of the six steps necessary for a successful metastasis.

Specific effects of artesunate that target metastasis include inhibition of NO production which is required for angiogenesis and inactivation of transcription factor NF-kappa B which is activated by inflammation and regulates essential processes for CFC progression. Artesunate decreases proteolytic enzymes matrix-metalloproteases (MMPs,) MMP-2 and MMP-9 which the CFCs need to degrade structures between cells that hold them together. This then allows them to invade adjacent tissues. Artesunate helps to keep the CFCs “stuck” by increasing E-cadherin, the protein responsible for attaching cells and maintaining normal tissue structure.


Epigenetics

The prefix, “epi…” means “above or around” or “in addition to” and the root word, “genetics” refers to the DNA. When referring to these phenomena in biology, epigenetics is understood to be the study of heritable traits, or a stable change of cell function, that happen without changing the DNA sequence. The study of epigenetics involves understanding how behaviors and the environment cause changes that affect the way genes work. Unlike genetic changes, epigenetic changes are reversible and do not change your DNA sequence, rather, they change how a specific DNA sequence is read. This is called gene expression and refers to how often or when certain proteins are to be produced as per the instructions from the genes. While genetic changes can alter which protein is made, epigenetic changes affect gene expression to turn genes “on” and “off”. Since the environment and behaviors, including diet, sleep habits, relationships, stresses, and exercise, can produce epigenetic changes, the connection between how genes work and do their job is greatly influenced by behavior and environment.

Therefore, epigenetics can either enhance tumor progression, decrease its aggressiveness, or turn it off completely by “rewriting” which genes are to be active, and which are not to be active and hence, could produce results such that CFCs are no longer malignant and return to normal. It must be kept in mind that “genetic expression” is malleable and changeable by responding to the microenvironment around the cell. Epigenetic changes are not permanent genetic changes such as would be the case with a genetic mutation. The field of epigenetics has grown tremendously because this process occurs in many situations other than with CFCs, as well. Clearly then, modifying the epigenetics is an important therapeutic modality. Also, CFCs arise initially as a result of epigenetic changes in response to changing metabolic requirements of the cell due to the microenvironment, i.e., the contents of the fluid in which the cells live. Hence, CFCs arise mostly from epigenetic changes rather than mutations, and therefore, the “genetic” components of CFCs are reversible, not permanent, especially if the appropriate substance or substances are administered. This includes the food, water, air, ability to manage stress, as well as the administration of substances like artesunate, ascorbate (vitamin C), curcumin, etc. 

Artesunate has been found to target many genes that are regulated differently in CFCs. These include epidermal growth factor receptor (EGFR) and human epidermal growth factor type II, also known as HER-2, both of which are decreased by artesunate. EGFR and HER-2 are often overexpressed on breast CFCs and are thereby targets of many drugs such as Herceptin and Perjeta, as well as botanical substances like artesunate. Artesunate and other artemisinins also have been shown to activate p53 and p21 tumor suppressor genes that are silenced in CFCs to prevent apoptosis so that they can return to their job of suppressing tumor development and growth.


Mitochondria

Mitochondria are organelles inside cells that are responsible for the energy production of the cell utilizing glucose and oxygen. Since oxygen easily produces reactive oxygen species (free radicals), they are the most vulnerable part of the cell that are easily affected by toxins and disruptive frequencies. Mitochondria play a central role in the development of CFCs as they become damaged and dysfunctional early on which requires the cells to adapt in order to survive by using another way to generate energy (fermentation). 

Artesunate disrupts (depolarization) the membrane potential of CFC mitochondria which leads to the destruction of the mitochondria, and eventually to the death of the whole cell. Interestingly and importantly, this does not occur in healthy cells that have properly functioning mitochondria.


Radiation and Chemotherapy Sensitizer

Artesunate and other derivatives have been shown to sensitize CFCs to radiation therapy and chemotherapy thus improving the effectiveness of those chemicals and radiation. This has been demonstrated in studies where artesunate has been used in conjunction with conventional treatments against a variety of types of CFCs including cervical, esophageal, liver, ovarian, and lung.


Reverses Multi-drug Resistance 

Resistance to treatment means that the CFCs are no longer able to be killed by chemotherapy, which is a major contributor to the failure of this type of treatment, its recurrence, and therefore the high mortality rate. Artemisinin, artesunate, and dihydroartemisinin have been shown to restore the sensitivity of CFCs to chemotherapy so that the chemotherapy can once again destroy the CFCs. This is not long-lived, of course since the underlying cause has not been discovered or eliminated and, also the CFC stem cells are unharmed by either chemotherapy or radiotherapy.


Modification Of The Immune System

The immune system is designed to identify and eliminate any cells that have become abnormal, such as CFCs. This is the inherent ability of the body to protect itself.  CFCs are very clever and have devised many ways to suppress, modify, and hide from the immune system. In the presence of immune dysfunction caused by CFCs, therapies that modulate the immune system are required to restore optimal immune function in order to eliminate CFCs and then, perhaps the most difficult of all, to keep them gone.

Artemisinin, artesunate, and other derivatives are able to target and then modify the immune system to help restore its ability to eliminate CFCs. Artesunate and its derivatives can silence the immune suppressive signals produced by the CFCs and activate several other types of immune cells to attack and eliminate the tumor.

Artesunate prevents tumor-associated macrophages from infiltrating to the tumor microenvironment. This is exceedingly important because once the macrophages, called M1 macrophages come into close contact with the tumor microenvironment (TME), instead of attacking the tumor, they turn into M2 macrophages that then support the growth and metastasis of CFCs. Artesunate also inhibits the secretion of pro-inflammatory cytokines TNF-α and IL-6 by macrophages. 

Artesunate has been shown to significantly enhance the activity and ability of natural killer (NK) cells to eliminate CFCs by decreasing the immunosuppressing signals of transforming growth factor-β1 (TGF-β1) and IL-10. NK cells are essential immune cells for protection against CFCs as they can recognize and kill CFCs directly, which means they do not need specific antigens to recognize CFCs, unlike other immune cells such as T lymphocytes. Most CFCs remove antigens called major histocompatibility complex 1 (MHC-I) from their cell surface and therefore can prevent CD8+T lymphocytes (activated lymphocytes) from recognizing them. This is how they can disguise themselves in plain sight. Highly active NK cells are therefore an essential component of the immune response to eliminate CFCs.

Artesunate is also known to be effective in calming an intense immune response called “cytokine storm”, which although can be caused by infections, anything that overwhelms the immune system such as many of the conventional CFC “treatments” such as high-dose chemotherapy, radiation and even surgery. The damage caused by these treatments results in excessive production of molecules secreted from the immune within the body (endogenous), resulting in tissue injury and cell death (necrosis). This then triggers inflammation that is mediated by Toll-Like Receptors (TLR) belonging to a large family of “pattern recognition receptors” (PRRs) found mostly on DC cells and macrophages that recognize viruses, bacteria, parasites, and fungi, as well as CFC debris from dead (necrotic) cells, which then activate both the innate and adaptive immune system cells. The result is the release of inflammatory cytokines such as NF-κB, and interferon-β (TRIF), which in turn can cause a huge imbalance. And, whenever an imbalance like this occurs, a surge in the pro-inflammatory mediators gets released into the blood such as interleukin (IL)-2, IL-4, IL-6, IL-1β, IL-8, interferon (IFN)-γ, tumor necrosis factor (TNF)-α. It has been found that IL-6 and IL-1β are one of the main initiators of a wave of cytokines, which find their way to other organs, resulting in multiple organ failure and death. This is a cytokine storm.

Furthermore, the stimulation of a receptor TLR-4 by high-dose chemotherapy has been shown to promote the growth of CFCs and initiate the metastatic spread of CFCs. Studies indicate that artesunate inhibits this TLR-4-triggered immune response by inhibiting the production of TLRs and preventing the release of inflammatory cytokines.

In addition, artesunate inhibits the activation of NF-kappaB which is another key regulator of systemic inflammation, and it is highly active in CFCs.

Together with vitamin C, curcumin, and quercetin, which all target and neutralize NF-κB, and many other inflammatory cytokines, this tragic outcome can be avoided.

Read more Collapse

References

Cui C, Feng H, Shi X, Wang Y, Feng Z, Liu J, Han Z, Fu J, Fu Z, Tong H. 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 Jul;27(1):110-21. doi: 10.1016/j.intimp.2015.05.004. Epub 2015 May 12. PMID: 25978851.

Efferth T. From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin Cancer Biol. 2017 Oct;46:65-83. doi: 10.1016/j.semcancer.2017.02.009. Epub 2017 Feb 28. PMID: 28254675.

Geng B, Zhu Y, Yuan Y, Bai J, Dou Z, Sui A, Luo W. Artesunate Suppresses Choroidal Melanoma Vasculogenic Mimicry Formation and Angiogenesis via the Wnt/CaMKII Signaling Axis. Front Oncol. 2021 Aug 12;11:714646. doi: 10.3389/fonc.2021.714646. Erratum in: Front Oncol. 2022 Mar 01;12:870805. PMID: 34476217; PMCID: PMC8406848.

Greenshields AL, Fernando W, Hoskin DW. The anti-malarial drug artesunate causes cell cycle arrest and apoptosis of triple-negative MDA-MB-468 and HER2-enriched SK-BR-3 breast cancer cells. Exp Mol Pathol. 2019 Apr;107:10-22. doi: 10.1016/j.yexmp.2019.01.006. Epub 2019 Jan 17. PMID: 30660598.

Huang Z, Gan S, Zhuang X, Chen Y, Lu L, Wang Y, Qi X, Feng Q, Huang Q, Du B, Zhang R, Liu Z. Artesunate Inhibits the Cell Growth in Colorectal Cancer by Promoting ROS-Dependent Cell Senescence and Autophagy. Cells. 2022 Aug 9;11(16):2472. doi: 10.3390/cells11162472. PMID: 36010550; PMCID: PMC9406496.

Innao V, Rizzo V, Allegra AG, Musolino C, Allegra A. Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma. Cells. 2021 Feb 19;10(2):439. doi: 10.3390/cells10020439. PMID: 33669515; PMCID: PMC7922387.

Luo J, Zhu W, Tang Y, Cao H, Zhou Y, Ji R, Zhou X, Lu Z, Yang H, Zhang S, Cao J. Artemisinin derivative artesunate induces radiosensitivity in cervical cancer cells in vitro and in vivo. Radiat Oncol. 2014 Mar 25;9:84. doi: 10.1186/1748-717X-9-84. PMID: 24666614; PMCID: PMC3987175.

Krishna S, Ganapathi S, Ster IC, Saeed ME, Cowan M, Finlayson C, Kovacsevics H, Jansen H, Kremsner PG, Efferth T, Kumar D. A Randomised, Double Blind, Placebo-Controlled Pilot Study of Oral Artesunate Therapy for Colorectal Cancer. EBioMedicine. 2014 Nov 15;2(1):82-90. doi: 10.1016/j.ebiom.2014.11.010. PMID: 26137537; PMCID: PMC4484515.

Peng J, Zhou J, Sun R, Chen Y, Pan D, Wang Q, Chen Y, Gong Z, Du Q. Dual-targeting of artesunate and chloroquine to tumor cells and tumor-associated macrophages by a biomimetic PLGA nanoparticle for colorectal cancer treatment. Int J Biol Macromol. 2023 Jul 31;244:125163. doi: 10.1016/j.ijbiomac.2023.125163. Epub 2023 Jun 2. PMID: 37270126.

Roh JL, Kim EH, Jang H, Shin D. Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol. 2017 Apr;11:254-262. doi: 10.1016/j.redox.2016.12.010. Epub 2016 Dec 18. PMID: 28012440; PMCID: PMC5198738.

Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C. Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies. Front Immunol. 2020 Jul 10;11:1708. doi: 10.3389/fimmu.2020.01708. PMID: 32754163; PMCID: PMC7365923.

Wang Z, Wang Q, He T, Li W, Liu Y, Fan Y, Wang Y, Wang Q, Chen J. The combination of artesunate and carboplatin exerts a synergistic anti-tumour effect on non-small cell lung cancer. Clin Exp Pharmacol Physiol. 2020 Jun;47(6):1083-1091. doi: 10.1111/1440-1681.13287. Epub 2020 Mar 20. PMID: 32072678.

Wen L, Liu L, Wen L, Yu T, Wei F. Artesunate promotes G2/M cell cycle arrest in MCF7 breast cancer cells through ATM activation. Breast Cancer. 2018 Nov;25(6):681-686. doi: 10.1007/s12282-018-0873-5. Epub 2018 May 24. PMID: 29797234.

Zhang W, Du Q, Bian P, Xiao Z, Wang X, Feng Y, Feng H, Zhu Z, Gao N, Zhu D, Fan X, Zhu Y. Artesunate exerts anti-prolactinoma activity by inhibiting mitochondrial metabolism and inducing apoptosis. Ann Transl Med. 2020 Jul;8(14):858. doi: 10.21037/atm-20-1113. PMID: 32793702; PMCID: PMC7396798.

 

Read more Collapse

You May Also Like

Ready To Redefine Your Views On Cancer Treatment?