Natural health products (NHPs) are defined as natural extracts containing polychemical mixtures; they play a leading role in the discovery and development of drugs, for disease treatment. More than 50% of current cancer therapeutics are derived from natural sources. However, the efficacy of natural extracts in treating cancer has not been explored extensively. Scientific research into the validity and mechanism of action of these products is needed to develop NHPs as main stream cancer therapy. The preclinical and clinical validation of NHPs would be essential for this development. This review summarizes some of the recent advancements in the area of NHPs with anticancer effects. This review also focuses on various NHPs that have been studied to scientifically validate their claims as anticancer agents. Furthermore, this review emphasizes the efficacy of these NHPs in targeting the multiple vulnerabilities of cancer cells for a more selective efficacious treatment. The studies reviewed here have paved the way for the introduction of more NHPs from traditional medicine to the forefront of modern medicine, in order to provide alternative, safer, and cheaper complementary treatments for cancer therapy and possibly improve the quality of life of cancer patients.
Natural health products (NHPs) and natural products (NPs) play a leading role in the discovery and the development of drugs for the treatment of human diseases. Traditional medicines in the Native American, Chinese, and Indian cultures have utilized numerous natural products, including dozens of spices and plant extracts. Scientific research into the validity of these traditional products has shown that many do indeed have potent anticancer effects [
Curcumin, the active ingredient in turmeric, has been widely studied for its anticancer properties. Turmeric (
Sources of anticancer drugs from the 1940s to 2010. ∗Natural product (N), derived from a natural product, usually a synthetic derivative (ND). Natural product “Botanical” (NB); natural product mimic (NM); totally synthetic drug (S) made by total synthesis, but the pharmacophore is/was from a natural product (S∗).
The discovery of the anticancer activities of so many traditional medicines and natural products has been supported by scientific evidence and validation. This was in part successful due to the initiation of the Cancer Chemotherapy National Service Center (CCNSC) in 1955, by the National Cancer Institute (NCI). The mandate of this program was to screen for antitumor agents on a larger scale by establishing a strict standardized protocol for testing potential anticancer compounds [
Since the 1980s, research into the anticancer effects of natural products has yielded many promising results. For example, resveratrol, a polyphenol present in grapes, shows potential as both a preventative and an antitumor agent [
Even with all the incoming evidence, herbal drugs and other NHPs and NPs are usually shunned during systemic chemotherapy because of herb-drug interaction and exaggeration of chemotherapy-related toxicity. Current research is focused on the development of new and more effective chemotherapeutic agents that have little to no associated toxicity to the patient. Lately, this focus has been centered on NHPs and herbal formulations, mainly in the form of plants and other biological sources around the world. NHPs have been used for centuries by a variety of cultural backgrounds for a great number of illnesses; some of which continually provide new medicinal applications and intriguing anecdotal evidence, which merits further investigation. Today, there are numerous natural health products that fall under the umbrella of traditional medicine, such as the Indian herbs Tulsi (
Another example of an NHP that has been used for centuries is the extract of dandelion, a perennial weed known for its curative properties. The dandelion species have been used in many traditional and modern herbal medicinal systems and this use has been documented all across the continents. Various parts of this plant have been used in the treatment of different ailments, with the root being used in gastrointestinal diseases and the leaves as a diuretic and digestive stimulant. The whole plant has been taken as a cure for hepatitis and anorexia as well, although some of the claims associated with this weed have gone unsubstantiated [
The different hallmarks of cancer and tumor cells include evading growth suppression signals, evading programmed cell death processes, inducing angiogenesis, and sustaining proliferative signaling, to name a few [
It is well-known that the inflammatory response is vital in living organisms for their protection against foreign matter. Inflammation more commonly occurs in cases of infection and injury (acute inflammation), but in certain situations, a more persistent, deregulated, and maladaptive inflammation (chronic inflammation) can arise. This chronic form of inflammation is usually associated with chronic diseases like cancer, where there is exacerbation of the disease, due to the prolonged inflammatory response. This would lead to increased proliferation of the cancer cells, increased angiogenesis, and promotion of metastatic capabilities [
It has been found that there is a shared pathology between cancer and inflammatory diseases, which is displayed in the gene expression signatures for cancer and those for inflammatory diseases [
Long pepper or
In addition to long pepper and piperlongumine, a natural compound found in grapes, peanuts, and berries known as
Dandelion extracts have been found to have anti-inflammatory activity in some cancer cells [
These findings suggest a great potential for NHPs with anti-inflammatory activity in the fight against cancer. The ability of these NHPs to target multiple pathways in inflammation and in cancer progression provides a potentially more efficacious way to selectively target cancer cells.
It has long been known that the mitochondria play a significant role in the carcinogenesis and cancer progression [
A lot of research has gone into antioxidant mechanisms and the roles they play in tumor development. Some of this work has provided better understanding of NHPs in oxidative stress response, especially in cancer development and treatment. There are increasing numbers of NHPs that are involved in oxidative stress response. One famous compound, piperlongumine, discussed above, has been shown to target and inhibit the endogenous oxidative stress response of cancer cells, leading to an increase in the levels of ROS and a corresponding increase in oxidative stress. The inability of the cells’ oxidative stress response to detoxify these reactive oxygen entities led to the induction of apoptosis in cancer cells. This effect was countered by the presence of the antioxidant, N-acetylcysteine. More importantly, this effect on ROS generation and oxidative stress pathway targeting was not observed in the noncancerous cells, suggesting a dependence on the oxidative stress response pathway in cancer cells [
Some NHPs are proposed to contain both antioxidant and prooxidant properties. Dandelion (
Lots of studies have been carried out with other NHPs; for instance, epigallocatechin-3-gallate (EGCG) has been studied for its antioxidant capabilities for decades and treatment with this compound significantly slowed down the growth of breast cancer tumors in mice [
There are a lot of characteristics attributed to curcumin and its role as an anticancer agent. Curcumin, from turmeric, is another natural compound that has both antioxidant and prooxidant characteristics and this capability has been studied in various cell culture models and confirmed in
Even with advances in NHP research, we are still a long way from understanding the connections between some of these NHPs and oxidative stress, especially in cancer research. It is therefore essential to further investigate how NHPs are able to distinguish between different conditions and act in accordance to both scavenge and induce the production of radical oxygen species.
Abnormal and excessive signal transduction is a common hallmark of cancer cells. This is in part due to the ability of these cell types to upregulate the expression of both receptors and the ligands (usually growth factors) required to transmit downstream signals. This ability thereby confers hyperproliferative characteristics to cancer cells; for instance, this is observed in aberrant Ras and myc signaling [
One particularly interesting class of compounds is the sesquiterpene lactones (SLs), found in an initial screen by the National Cancer Institute (NCI), the same screening that led to the identification of Taxol [
Natural health products that target the angiogenesis pathways.
NHPs/NPs | Target (decrease) |
---|---|
|
VEGF/KDR |
|
VEGF |
|
|
|
MMP-2/9 |
|
VEGF |
|
PGDF |
|
MMP-2 |
Quercetin | COX-2 |
|
VEGF |
|
VEGF |
|
VEGF |
|
HER2 |
Soy isoflavones (genistein, daidzein) | EGFR (HER1) |
|
HER2/neu |
Omega-3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid) | COX-2 |
|
COX-2 |
|
COX-2 |
|
COX-2 |
Several other receptors play a role in the progression of cancers, especially the estrogen (ER) and androgen receptors (AR) which are seen in breast and prostate cancers [
Perhaps the most common example of an ER antagonist is tamoxifen, which is used especially for hormone-receptive breast cancer treatment. Recent studies have shown that administration of soy isoflavones, such as genistein and daidzein, can have an effect on the efficacy of tamoxifen. Some studies suggest that some isoflavones (genistein) can increase the potency of tamoxifen in ER− breast cancer cells and have the opposite effect in ER+ cells, while others indicate that daidzein, in combination with tamoxifen, has increased protection against both ER+ and ER− breast carcinomas [
Several NHPs have been shown to induce different types of programmed cell death, including apoptosis, necrosis, and autophagy, in cancer cells, some in a selective manner. However, understanding the mechanism of action of these NHPs sometimes proves difficult, as the multiple components tend to have multiple targets. This has led to increasing mechanistic studies into effective NHPs and some of these studies have identified active NHPs with receptor antagonistic activities. For instance, withaferin A, a naturally occurring bioactive component isolated from
As mentioned earlier, several compounds found in soy isoflavones have significant anticancer activity, with genistein and daidzein’s ability to target HER2/neu and EGFR, to inhibit angiogenesis [
Another source of bioactive components is the long pepper, from the genus
Aside from receptors involved with increased gene expression and cell growth and proliferation, death receptors are also key players in normal and cancer cell growth and survival. These receptors belong to the tumor necrosis factor (TNF) superfamily of receptors that play a role in signaling cell death and survival pathways and include TNFR1/TNF-
Studies have shown that several NHPs are able to target death receptor signaling pathways, again confirming their usefulness as potential anticancer agents. The selective anticancer efficacy of dandelion root extract has been attributed to its ability to induce death-receptor mediated extrinsic apoptosis in cancer cells selectively [
Taxanes (e.g., paclitaxel and docetaxel), isolated from Taxus, are effective as cytotoxic agents, as they target and stabilize the microtubules and prevent their depolymerization thereby interfering with normal cell functions and induce apoptosis. Further studies on the mechanism of taxanes indicate that these compounds can induce the expression of TNF-
Curcumin, discussed in previous sections of this review, has shown significant anticancer activity in several cancer cells, with the ability to target multiple signaling pathways. Not only does it antagonize cell surface receptors, like the epidermal growth factor receptor (EGFR), but it has also been shown to induce apoptosis in human melanoma cells through the activation of the Fas receptor and subsequent activation of caspase-8 [
These indications of the roles of NHPs and NPs as agonists and antagonists of receptors for the selective targeting of cancer cells to the process of cell death give further validation to the use of these products as safer alternatives to current cancer treatments. However, these examples also indicate that there is a lot of work that is required to further understand how these NHPs/NPs are able to recognize the aberrant signaling system in cancer cells and exploit these differences and vulnerabilities, although these studies provide a stepping stone for future validation of NHPs in the mechanistic validation of selective targeting of cancer cells for programmed cell death processes.
NHPs are usually complex mixtures that contain many bioactive substances. Dosage forms are difficult to characterize, as traditional preparation, dosage, and usage do not account for the presence of the various bioactive components. It is therefore imperative that identification of pharmacologically active ingredients within any NHP is carried out. As mentioned earlier,
Compounds identified in standardized GMP decoction of dandelion roots by UPLC MS QTOF.
Compound | Molecular formula | Monoisotopic mass |
---|---|---|
4-Hydroxybenzoic acid | C7H6O3 | 138.0316941 |
Sucrose | C12H22O11 | 342.1162116 |
Vernoflexuoside | C21H28O8 | 408.1784179 |
Pollinastanol | C28H48O | 400.3705162 |
Austricin | C15H18O4 | 262.1205091 |
Lycoperodine 1 | C12H12N2O2 | 216.0898776 |
11-beta, 13-dihydrolactucin | C15H18O5 | 278.1154237 |
Cichorioside C | C21H32O9 | 428.2046326 |
Taraxafolide | C21H28O10 | 440.1682471 |
Sonchuside A | C21H32O8 | 412.209718 |
Annuolide D | C15H20O3 | 248.1412445 |
Notoserolide A | C21H28O9 | 424.1733325 |
Taraxacin | C15H14O3 | 242.0942943 |
Taraxinic acid beta-D-glucopyranosyl ester | C21H28O9 | 424.1733325 |
Using standard pharmacognosy methods for the identification of active principles, identification of active principles can be achieved. These studies provide the backbone that is required to ensure standardization of NHPs that could be beneficial in the treatment of diseases, especially cancer.
In conclusion, antiproliferation activity has been found in both (water) polar and nonpolar (ethanolic) fractions of many NHPs, for instance, with dandelion root extracts, which contain sesquiterpenes, phenolics, and triterpenes [
With all the evidence put forward in the previous sections of this review, it stands to reason that the multiple components present within an NHP play a role in and are responsible for the selective efficacy of these NHPs against cancer cells,
Extensive scientific validation will be required to determine the efficacy, safety, and mechanism of action of the combined treatment options for the effective treatment of cancer. The effectiveness of these NHPs may be increased when multiple agents are used in optimal combinations.
The whole purpose of the scientific validation of NHPs against diseases, especially cancer, is to provide awareness for these NHPs and NPs that have been used for centuries in various traditional medicines. The scientific studies carried out provide the necessary evidence regarding the efficacy of these NHPs, their indications and contraindications, and information on their safe and effective use. In Canada, Health Canada is the governing agency for the introduction of drugs and NHPs to the public, with divisions completely dedicated to NHPs, the Natural Health Product Directorate (NHPD), and the Therapeutic Product Directorate (TPD). These divisions were generated to assist and ensure that Canadians have access to NHPs that are “safe, effective, and of high quality, while respecting freedom of choice and philosophical and cultural diversity.” Regulations for NHPs came into effect in 2004 and take into account their unique nature and characteristics. At the end of 2012, the NHPD published information that outline how NHPs are assessed, with a focus on health claims, the use of risk information, and the use of NHPs in combination; these include the “Pathway for Licensing NHPs Making Modern Health Claims”, “Pathway for Licensing NHPs making Traditional Health Claims” and “Quality of Natural Health Products Guide”, which summaries the requirement for standardization of high quality NHPs. Even after clinical trials and progression to the market, Health Canada continues to collect information on adverse reaction reports for NHPs, to track and analyze these reaction reports for NHP use through the Canada Vigilance Program and other regulatory agencies, like the World Health Organization (WHO). This allows constant monitoring of NHPs to ensure continuous safety and efficacy associated with these forms of treatment. More information on application to Health Canada and requirements involved in getting an NHP to the market can be found at their website:
In the United States, the Food and Drug Administration (FDA) is the agency in charge of regulating the production and provision of NHPs to the public. NHPs are referred to as complementary and alternative medicine (CAM), which are divided into 5 main domains: whole medical systems; Ayurveda, homeopathic medicine, and traditional Chinese medicine (TCM). This is the most common domain of NHPs/CAMs, which requires vigorous reviews and validation by the scientific community, mind-body medicine; meditation, prayer, and creative therapies, such as dance, biologically based practices with herbs, foods, vitamins, and dietary supplements, manipulative and body-based practices; chiropractic and osteopathic manipulation and massage, energy medicine, including therapeutic touch.
These domains undergo the same levels of rigorous review, as described in the Health Canada review aspect above. More information on application to the FDA and their requirements can be found at their website:
These regulatory agencies ensure that health claims made by traditional medicine have scientific validations for anecdotal evidence presented for centuries. They ensure proper standardizations involved in the production and usage of NHPs/NPs/CAMs to maximize the benefits of these products and medicines.
The toll of cancer on the human body and the society as a whole indicates a serious need for a better selective, effective, and cheaper mode of treatment. Natural health products hold a great potential to provide nontoxic alternatives for the treatment of cancer. More importantly, NHPs as a complex polychemical mixture of pharmacologically active compounds may target multiple vulnerabilities of cancer cells, without toxicity to the noncancerous cells. The complete scientific and clinical evaluation of the potential NHPs are essential to bring these products to mainstream cancer therapies, in order to provide alternative, safer, and cheaper complementary treatments for cancer therapy and possibly improve the quality of life of cancer patients. With the health regulatory agencies, including Health Canada and the FDA providing the required regulatory framework for the development of NHPs for therapeutic purposes, the future will see the growth and expansion of many cancer-selective NHPs in mainstream cancer treatment.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors would like to acknowledge the various contributions from the following groups and individuals: the Couvillon family, the Lotte & John Hecht Memorial Foundation, the Knights of Columbus, Chapter 9671, The Pajama Angels, The Seeds4Hope Windsor Essex County Cancer Centre Foundation, and the Jesse & Julie Rasch Foundation. The work that the authors do is a direct result of the never-ending support they receive.