Artemisinin a class of remarkable drugs

Artemisinin and its derivatives are all sesquiterpene lactones containing an unusual peroxide bridge and they all derive from the annual sweet wormwood plant Artemisia annua L (also known as sweet wormwood, sweet annie, sweet sagewort, annual mugwort or annual wormwood), and originally they were used as Traditional Chinese Medicine for treating malaria and related symptoms such as fever and chills. Artemisinin's antimalarial properties are attributed to the unusual peroxide bridge it has.

Very briefly. The isolation and characterisation of artemisinin from A. annua in 1972 was followed by a Nobel Prize in Physiology or Medicine conferred to the Chinese scientist Youyou Tu in 2015 for discovering that a low-temperature extraction process could be used to isolate an effective antimalarial substance from the plant, and that drew worldwide attention to artemisinin.

Fifty years later, besides its well-established anti-malarial effects,

• artemisinin and

• its semi-synthetic derivatives (ARTs) namely: dihydroar-artemisinin (DHA), artesunate, artemether and arteether,

are studied nowadays for their potent anti-cancer activities, initially reported in 1993 (Source 2019: "Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine"). But apart malaria, that remains the only disease for which artemisinin is an approved treatment, and the potential application of artemisinin in anti-cancer therapy, artemisinin and ARTs have also anti-inflammatory, anti-parasitic (outside of malaria) and anti-viral roles.

In particular, the anti-cancer effects of DHA and artesunate (the two most studied ART derivatives for cancer treatment) were demonstrated in a broad spectrum of cancer cell lines including lung, liver, pancreatic, colorectal, esophageal, breast, ovarian, cervical, head and neck and prostate cancer.

So far, the anti-cancer activities of artemisinin and ARTs include:

• induction of apoptosis and cell cycle arrest, and
• inhibition of cell proliferation and growth, metastasis and angiogenesis.

We now know that ART/ARTs inhibit cell proliferation, migration and invasion and induce apoptosis in human breast cancer cells (through release of cytochrome c and caspase-9 cleavage); that induce apoptosis in murine mastocytome cells (mast cells) and hamster kidney adenocarcinoma cells; and that inhibit tumour growth in mastocytome xenograft mice. For example, DHA suppresses cell growth through cell cycle arrest and apoptosis in human hepatocellular carcinoma cell lines (in vitro) and hepatocellular carcinoma xenograft mice (in vivo).

Moreover, autophagy plays a vital role in ART-mediated anti-cancer activities.

Autophagy (or autophagocytosis) is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. So, the literal meaning of autophagy is “self-eating” and according to Priya Khorana, PhD, in nutrition education from Columbia University autophagy is the body's way of cleaning out damaged cells or components, in order to regenerate newer, healthier cells.

Specifically, DHA can induce autophagy-dependent cell death in human cervical cancer cells, cholangiocarcinoma (bile duct cancer) and tongue squamous cell carcinoma, while ARTs induce autophagy-mediated cell cycle arrest in human ovarian cancer cells.

The autophagy-dependent induced cell death by DHA is mediated by suppressing the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) protein complex that controls transcription of DNA, in several cancer cell lines including B lymphocytes, colon cancer and cervical cancer.

NF-κB, that is found in almost all animal cell types, plays a key role in regulating the immune response to infection and is involved in cellular responses to stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidised LDL and bacterial or viral antigens. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development.

Furthermore, ART/ARTs can also inhibit metastasis in various cancer cells such as non-small-cell lung carcinoma, ovarian and lung cancer cell lines. And apart from apoptosis and metastasis, the inhibition of angiogenesis is also a crucial approach in cancer treatment with ART/ARTs.

For example, ART/ARTs inhibit angiogenesis (neo-vascularisation) through mitogen-activated protein kinase (MAPK) activation in osteosarcoma (MAPK are highly conserved proteins in eukaryotes and are involved in signal transduction pathways that modulate physiological and pathophysiological cell responses). Whilst DHA exerts strong anti-angiogenic effect by repressing extracellular signal–regulated kinase/ERK (widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis and post-mitotic functions) and NF-κB pathways in human umbilical vein endothelial cells and pancreatic cancer, respectively.

For more information about inhibition of angiogenesis please check: "Fighting angiogenesis with natural compounds backed by science" Via Vocal.

To boot, another mechanism of killing tumour cells by ARTs is the iron-dependent cell death called ferroptosis, a new form of cell death and therefore an attractive strategy for anti-cancer treatment.

Ferroptosis, a type of programmed cell death dependent on iron and driven by iron overload and lipid peroxidation, is genetically and biochemically distinct from apoptosis.

Recent work (Review: "Artemisinin, the Magic Drug Discovered from Traditional Chinese Medicine") linked artemisinin-induced cytotoxicity and lysosomal function, in contributing to this iron-dependent form of cell death.

Specifically, lysosome-mediated degradation of ferritin (the universal intracellular protein that stores iron and releases it in a controlled way) under autophagy conditions (termed ferritinophagy: a selective type of autophagy, which induces ferroptosis by degrading ferritin and inducing iron overload), releases free ferrous iron. Which in turn contributes to both ferroptosis of cancer cells and iron-mediated generation of ROS. Moroever, autophagy itself is a cellular process that is reportedly activated by artemisinin.

Interestingly, ART is demonstrated to be an inhibitor of the anti-cancer target histone deacetylases (HDAC).

HDAC are a class of enzymes that remove the acetyl groups from an amino acid on a histone and this is very important because the DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation.

In particular, treatment with artemisinin inhibited cell proliferation of estrogen receptor negative breast cancer cells and additionally artemisinin strongly inhibited cancer cell migration and invasion. Overall, the expression of genes involved in the signalling pathways associated with proliferation, migration, invasion and apoptosis were significantly altered by artemisinin, which cooperatively resulted into reduced growth promoting activities of breast cancer cell lines. Interestingly, artemisinin exhibited inhibitory effect on HDACs.

Other studies have shown the synergistic effects of ART/ARTs with other compounds or therapeutic approaches.

The combined treatment of ART and the naturally occurring polyphenolic compound found in grapes resveratrol (for more information about resveratrol as anti cancer therapy please check: Via Vocal, Via Vocal) markedly inhibited cell proliferation and migration, and enhanced apoptosis and ROS production in human cervical cancer cell line and hepatocellular carcinoma cell line.

Likewise, the combined use of DHA and gemcitabine (a chemotherapy drug used as a treatment for different types of cancer, including bladder and breast cancer) exhibited strong synergistic effects on the loss of mitochondrial membrane potential and induction of apoptosis in human non-small cell lung cancer cell line.

DHA also reinforces the anti-cancer activity of chemotherapeutic agent, cisplatin, in cisplatin-resistant ovarian cancer cells. Cisplatin is a chemotherapy medication used to treat a number of cancers like testicular, ovarian, cervical, breast, bladder, head and neck, esophageal and lung cancer; and mesothelioma, brain tumours and neuroblastoma.

However, ART has poor water solubility and bioavailability.

So, in order to solve this issue ART is encapsulated into micelles to form ART-loaded micelles. These ART-loaded micelles, for example enhance the drug exposure time and accumulation in breast cancer xenograft mice (in vivo), and shows specific toxicity in human and murine breast cancer cell lines (in vitro). Moreover, dimmers of ART are also synthesised by polyamine linkers, and they further inhibit cell proliferation in human breast cancer cell lines and angiogenesis in human umbilical vein endothelial cell line.

Another artemisinin analog is Artenimol-R, that was shown to improve clinical symptoms and tolerability in patients with advanced cervical cancer.

But now let's talk about Artesunate.

Artesunate is a semi-synthetic compound derived from artemisinin, that exerts better water solubility and higher oral bioavailability, that makes it a better candidate for anti-cancer therapy in bladder, breast, cervical, colorectal, esophageal, gastric, ovarian and prostate cancer, renal carcinoma ("Fighting renal cell carcinoma with natural compounds backed by science" Via Vocal), leukemia, melanoma and multiple myeloma.

Its anti-cancer effects include induction of cell cycle arrest (in human breast cancer, ovarian cancer cell lines) and apoptosis (human breast, gastric cancer, colorectal cancer, esophageal cancer cell lines), inhibition of cell proliferation and growth, metastasis and angiogenesis. Artesunate is inducing also autophagy in human colorectal cancer cell lines, and the inhibition of autophagy enhances artesunate-mediated apoptosis. Similarly, artesunate-induced mitophagy provides a protective effects against cell death in human cervical cancer cell lines.

Moreover, artesunate inhibits cell invasion and migration in human prostate cancer, cervical cancer and melanoma cell lines, and suppresses tumor angiogenesis in human umbilical vein endothelial cells (in vitro) and renal carcinoma xenograft mice (in vivo).

--------------------------

To date, artemisinin derived drugs have been used for the treatment of malaria and except for two case reports, no major side effects have been reported in humans at doses used for the treatment of malaria but it is still unknown whether the higher doses required for anti-cancer therapy could cause major side effects.

For example, some people use 4.5 to 9 grams of the dried Artemisia annua herb in boiling water as a tea infusion to help treat fever and malaria.

Others use 100 to 200 milligrams of artemisinin, in combination with other therapies, to treat the disease.

However, people may experience the following side effects: a skin rash after topical use, dizziness, ringing in the ears, vomiting, nausea, tremors and liver problems.

Regarding cancer, so far the in vivo studies showed that doses of artemisinin of at least 5 times higher than those used for antimalaria therapy are required in order to induce an effect in anti-cancer therapies. Unfortunately, the safety of such doses has not yet been evaluated in Phase I clinical trials.

Finally, since artemisinin might interact with anti-seizure medications, so speak to a doctor before taking any form of artemisinin.

Thank you for reading 👓💙

And if you liked this post why not share it?

#health #cancer #drugdiscovery #nature

PS:

As Thích Nhất Hạnh the Vietnamese Thiền Buddhist monk and peace activist (historically recognised as the main inspiration for engaged Buddhism) once said:

“Drink your tea slowly and reverently, as if it is the axis on which the world earth revolves–slowly, evenly, without rushing toward the future.”