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Artemisinin: Artemisinin and its derivatives are commonly used anti-malarial drugs that have been shown to have anti-neoplastic properties.  Artesunate is a semi-synthetic derivative of artemisinin that comes from the Chinese herb sweet wormwood. Artesunate has been proven as an effective cytotoxic agent against ovarian, breast, colon, melanoma, leukemia, renal, and prostate cancer cell cultures.  Artesunate can also induce apoptosis in a variety of cancer cell lines.  Artesunate prompts cell cycle arrest in the G2/M phase by increasing the expression of the initiator of autophagy, specifically Beclin 1.¹⁶ Some evidence suggests that artesunate may cause cell cycle arrest and apoptosis in some breast cancer cell lines, including triple negative breast cancer.¹⁷ The low toxicity profile and long history of use of artemisinin for malaria world-wide make this substance and its derivatives a very interesting source of anti-cancer therapeutics.¹⁸  Dosing varies based on oral or IV administration.

Melatonin: Melatonin is a ‘sleep hormone’ and neurotransmitter released by the pineal gland.  It is also a highly efficient antioxidant.  It is one of the prime regulators of our circadian rhythm and sleep.  Melatonin has been ascribed anti-inflammatory, immunomodulatory, pro-apoptotic, anti-proliferative, and anti-angiogenic properties that make it a powerful antitumor agent.  One effect that is garnering interest is melatonin’s ability to modulate inflammation and free radical expression through epigenetic on and off mechanisms.  The actions of melatonin are primarily mediated by the G-protein coupled MT1 and MT2 receptors.  The oncostatic action of melatonin is through multiple actions, including upregulation of apoptosis, the arrest of the cell cycle, inhibition of metastasis, and antioxidant activity.^18-20 Beyond supporting healthy sleep this molecule appears to have a wide variety of direct and indirect effects on cancer.  Dosing usually starts low (3-5 mg) taken right before bedtime, then it can be increased slowly as tolerated and tapered up to 240 mg or higher.  Dosing can be split up over the day as it increases and as is tolerated.

Milk Thistle: Milk thistle/Silymarin (Silybum marianum) has been traditionally used in medicine, particularly in the treatment of liver diseases.  Silimarin has been demonstrated to “inhibit cell proliferation and to induce apoptosis, while also having anti-angiogenic properties.” The induction of apoptosis in cancer cells has been mediated by the involvement of cellular stress.  Milk thistle has the potential to operate as a STAT3 inhibitor as well as an inhibitor of the upregulation of the PD-L1 protein, that can allow the cancer to hide from the immune system, which has been the target of some checkpoint inhibitors.  These influences may prevent cancer cell growth and immune system evasion.²¹ Silimarin appears to work on epithelial-mesenchymal transition (EMT) regulators, whereby epithelial cells are converted into mesenchymal cells, which are frequently activated during cancer invasion and metastasis—thus being a promising therapy for certain cancers, including non-small cell lung cancer. It has also been documented to suppress cancer cells by means of down-regulating actin cytoskeleton and PI3K/Akt molecular pathways.  Silymarin has been shown to help sensitize cancer cells to chemotherapy, and silymarin may also reduce the toxic effects of chemotherapy on vital organs or on healthy cells.^18,22 Hyperactivation of PI3K signaling cascades is one among the most ordinary events in human cancers.  Dosing ranges from 1,000-3,000 mg per day.

Berberine: Berberine is an isoquinoline alkaloid extracted from the root, rhizome, and stem of Rhizoma coptidis. Berberine contributes to cell death by inducing cancer cell apoptosis through different mechanisms.  Berberine contributes through multiple mechanisms to the inhibition of metastasis and cell invasion.¹⁸  Berberine decreases insulin resistance through upregulation of insulin receptor expression in normal cells.  Obesity, insulin resistance, and type 2 diabetes (T2D) increase the prevalence and worsens the prognosis of more than a dozen different cancer types.  Berberine appears to also provide protection for patients receiving radiation therapy.  Several signaling pathways are affected by berberine, including the MAP (mitogen-activated protein) kinase and Wnt/β-catenin pathways, which are critical for reducing cellular migration and sensitivity to various growth factors involved in promoting cancer cell proliferation.²³  Dosing ranges from 1,000-3,000 mg when taken orally.

Curcumin: Curcumin, a polyphenol extracted from the rhizomes of Curcuma longa, also known as turmeric,belongs to the most promising group of bioactive natural compounds, especially in the treatment of several cancer types.  Curcumin has a variety of pharmacological effects such as antioxidant, anti-cancer, anti-inflammatory, and anti-microbial activities. Anti- cancer effects of curcumin are due to targeting of a wide range of cellular and molecular pathways involved in cancer pathogenesis, including NF-kB, MAPK, PTEN, P53, and microRNAs (miRNA) network.^18,24 Curcumin extract taken orally can be dosed from 800-8,000 mg per day. IV curcumin has been used when in a liposomal delivery form, and those doses are usually much lower.

Quercetin: Quercetin is a naturally occurring flavonoid present in many commonly consumed food items. Quercetin glycosides are the dominant flavonoid content that can be found in propolis along with other healthy foods, including onion, broccoli, apple, tea, as well as red wine.  Quercetin governs numerous intracellular targets, including the proteins involved in apoptosis, cell cycle arrest, detoxification, antioxidant replication, and angiogenesis.  Quercetin may mediate apoptosis through several mechanisms, including mitochondrial disruption, DNA intercalation or down regulation of survival signals like PI3K/Akt and NFkappaB.²⁵ Quercetin has been shown to work well in combination with many chemotherapeutic agents.^26-28  Quercetin is a flavonoid with antioxidant properties. The ability of quercetin to exert many beneficial effects on health, including protection against various diseases such as osteoporosis, lung cancer, and cardiovascular disease makes it a flavonoid of great interest amongst integrative practitioners. Dosing varies but ranges between 400-1,600 mg, split up over several doses throughout the day.

Vitamin C (Ascorbic acid): Knowledge regarding the pharmacokinetic properties of ascorbic acid or vitamin C, has in recent preclinical studies, sparked interest in the utilization of high-dose vitamin C for cancer treatment.  Studies have shown that pharmacological vitamin C (doses given intravenously) targets many of the mechanisms that cancer cells utilize for their expansion and survival.  The main components of ascorbate-induced cell death are DNA double-strand breaks via the production of hydroxyl radical (H₂O₂) and ATP depletion due to the activation of poly (ADP-ribose) polymerase 1.^7,29,30 Some early animal studies have shown a synergy with some immunotherapy checkpoint inhibitors.³¹ Due to the general safety and tolerance of this vitamin, there is much excitement about its use alone and in conjunction with other modalities such as chemotherapy and CAM therapeutics.  Dosing of vitamin C given intravenously can range from 60-100 grams over several hours. 

Vitamin D: A low vitamin D status is associated with an increased risk of various cancers, such as of colon, breast, prostate and hematological cancers. Several epidemiological studies have suggested that ultraviolet-B exposure can help reduce cancer risk and prevalence, indicating a potential role for vitamin D as a feasible agent to prevent cancer incidence and recurrence.

vitamin D stimulates the innate immune system in fighting more efficiently against bacterial infections, such as tuberculosis, while it prevents overreactions of the adaptive immune system that may cause autoimmune diseases, such as multiple sclerosis.  Some of the strongest research evidence suggests it may play a role in cancer prevention.³² There have been two randomized controlled trials using vitamin D and calcium that found a beneficial effect in reducing cancer incidence.   One showed a clear relationship with supplemental vitamin D reducing the relative risk of breast cancer in post-menopausal women while the other from data from the Women’s Health Initiative study showed a significant decrease in breast cancer risk in vitamin D supplemented participants.^33,34 Dosing really is individualized to keep serum levels between 70-100 ng/ml and usually requires it be taken with K2 in order to maintain calcium homeostasis.

Our efforts in the field of integrative oncology have always been to focus on the personalization of care.  By providing individualized and patient-focused care, we believe that outcomes for both quality of life and length of life can be improved.  Many people have put off their preventative cancer screenings (colonoscopies, physical exams, etc.) over this past year due to COVID-19. We in the field of integrative medicine feel prevention and early intervention is critical in taming the beast that is cancer.

As we enter the era of precision medicine with our eyes on the horizon, we see molecular technologies like CRISPR Cas-9, personalized cancer vaccines, novel small molecules and individualized targeted therapies and the newly discovered Retron Library Recombineering (RLR) gene editing tool, offering hope to those who develop cancer in the future.  Like many things in this world, the future is never clear; however, this is an exciting time and some of that excitement comes in the form of repurposed medications and CAM therapies for the treatment of cancer.  By integrating some of these tools into oncology practices today, it might be possible to increase treatment efficacy and improve response rates for patients with a wide array of cancer types.  If you or someone you know is interested in using some of these tools to address a cancer diagnosis, please consult with your primary physician, oncologist, and integrative oncologist to learn more.  Never attempt to self-diagnose or self-treat any illness, including cancer, by yourself.  Cancer is a complex illness and requires a team of experts to accurately diagnose and treat.

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