Ginger (Zingiber officinale) is a well-known herb consumed as a spice and food as well as widely used as herbal medicine for various ailments. A number of biologically active ingredients including gingerols and its various derivatives have been identified and synthesized from ginger in recent years. One important class of derivatives are shogaols that are primarily the dehydrated products of gingerols and are found exclusively in dried ginger.
This newly -published study in PLoS reveals that the pungent component found within ginger, known as 6-shogaol, is way more potent in killing cancer stem cells than standardized chemotherapy. 6-shogaol has been shown to exert inhibitory effect on various cancer cell lines and animal disease models.
To check whether 6-shogaol is effective on breast cancer stem cells, researchers have generated model stem cell-like spheroids from 2 types of breast cancer cell lines, ER/PR positive MCF-7 and triple negative MDA-MB-231.
The cells were grown in low attachment plates with conditioned media that promote non-adherent growth. Under these conditions, the cells became subsequently organized as clusters of spherical cells. After 3 days of growth, the clusters were considered as stable spheroids. All the further experiments were performed under these conditions.
As we have discussed in greater detail in a previous article on the same topic, cancer stem cells are at the very root of a wide range of cancers (not only the breast cancer) and are sometimes referred to as “mother cells” since they are responsible for producing all the different “daughter cells” that constitute the tumor colony.
While cancer stem cells only constitute between 0.2 and 1% of the cells within any given tumor, they have the seeming “immortal” ability to renew themselves, are capable of continuous differentiation, are resistant to conventional chemotherapeutic agents, and are tumorigenic, i.e. are capable of “splitting off” to create new tumor colonies. Clearly, the cancer stem cells within a tumor must be destroyed if cancer treatment is to be announced “a lasting cure.”
The new study titled 6-Shogaol Inhibits Breast Cancer Cells and Stem Cell-Like Spheroids by Modulation of Notch Signaling Pathway and Induction of Autophagic Cell Death” identified powerful anti-cancer stem cell activity in 6-shogaol, a pungent constituent of ginger produced when the root is either dried or cooked.
The study also found that the cancer-destroying effects occurred at concentrations that were non-toxic to non-cancerous cells – a crucial difference from conventional cancer treatments that simply do not exhibit this kind of selective cytotoxicity and therefore can be very hazardous to the patient, depending on his immune response.
The authors of the study further affirm these important points: Cancer stem cells pose serious obstacle to cancer therapy success as they can be responsible for poor prognosis and tumor relapse. To add to the misery, very few chemotherapeutic compounds show probability to kill these cells.
Several researchers have shown that cancer stem cells are resistant to paclitaxel, doxorubicin, 5-fluorouracil, and platinum drugs. CSCs are thus an almost unreachable “population” in tumors for chemotherapy. Therefore any compound, that shows promise towards destroying cancer stem cells, is a highly desirable source towards future cancer treatments and should be followed up for urgent further development.
The researchers identified a variety of ways in which 6-shagoal targets breast cancer:
- It reduces the expression of CD44/CD24 cancer stem cell surface markers in breast cancer spheroids (3-dimensional cultures of cells modeling stem cell like cancer)
- It significantly affects the cell cycle, resulting in increased cancer cell death
- It induces programmed cell death primarily through the induction of autophagy, with apoptosis as a secondary inducer
- It inhibits breast cancer spheroid formation by altering Notch signaling pathway through γ-secretase inhibition.
- It exhibits cytotoxicity (cell killing properties) against monolayer (1-dimensional cancer model) and spheroid cells (3-dimensional cancer model)
It was in evaluating the last mode of 6-shagoal’s chemotherapeutic activity and comparing it to the activity of the conventional chemotherapeutic agent taxol that the researchers discovered an astounding difference. Whereas taxol exhibited clear cytotoxicity in the one-dimensional (flat) monolayer experimental model, it had virtually no effect on the spheroid model, which is a more “real world” model reflecting the 3-dimensionality of tumors and their stem cell “subpopulations.”
Amazingly, this proved to be true even when the concentration of taxol was increased by 4 orders of magnitude: “In contrast [to 6-shagoal], taxol, even though was highly active in monolayer cells, did not show activity against the spheroids even at 10,000 fold higher concentration compared with 6-shogoal.”
This is a highly significant finding, as it affirms a common pattern in cancer research that acknowledges the primary role of cancer stem cells: namely, while conventional techniques like surgery, radiation, and chemotherapy are effective at shredding a tumor size, sometimes to the point where it is “debulked,” burned,” or “poisoned” out of the body even below the threshold of re-detection, “winning of the battle” often comes at an expensive price.
Ultimately, the cancer stem cell population regrows the tumors, now with increased vengeance and metastatic invasiveness, resulting in the cancer “winning the war.”
The monolayer model, which does not account for the complex immunity of actual cancer stem-cell based tumors against chemo agents like taxol, represents the old preclinical model of testing cancer treatments. The spheroid model, on the other hand, clearly shows that even 10,000 times higher concentrations of taxol are not capable of beating this ginger component at selectively targeting the root cause of the tumor malevolence.
In their final remarks, the authors point out a hugely important distinction between natural anti-cancer agents and conventional ones that have only been introduced in the past half century or so, namely, “Dietary compounds are welcome options for human diseases due to their time-tested acceptability by human bodies.”
Unlike modern, synthetically-produced and patented chemicals, ginger, curcumin, green tea, and hundreds of other compounds naturally found in the human diet, have been “centuries-tested” as acceptable for the human body in the largest and longest running “clinical trials” known: the tens of thousands of years of direct human experience, including the thousands of different cultures from around the world, that constitute human prehistory as well.
These experientially-based “trials” are validated not by RCTs, or a peer-reviewed publication process, but by the fact that we all made it through this incalculably vast span of time to be “alive and kicking” here today. Consider also that if our ancestors made the wrong dietary choice by simply mistaking an edible berry for a poisonous one, the consequences could be deadly.
This places even greater practical significance on the “time-testing” of dietary compounds, which was not an academic affair, but rather a life or death affair, so, consequently, the information contained within various cultural traditions as “recipes” passed down from father to son, are “epigenetic inheritance systems” no less important for our lasting health.
Ultimately, this new study adds to a growing body of research indicating that targeting cancer-stem-cell approaches using natural substances present in the human diet for thousands of years are superior to chemotherapy and radiation, both of which actually increase the relative populations of cancer stem cells versus non-tumorigenic ones.