Upcoming Issue Highlights
Home Subscribe Advertise Sourcebook Free Product Info Home

The Relevance of Cancer Stem Cell Research and Botanicals for Integrative Practice

Cancer Stem Cell Cancer Stem Cell
EuroMedica
 
Longevity By Nature

There has been a long battle against cancer in conventional practice. The American Cancer Society, a non-profit organization dedicated to the elimination of cancer, was founded in 1913. In 1962, President John F. Kennedy announced that that was the year to make dramatic advancements against cancer.

And in 2013, Time magazine announced triumphantly that cancer was curable, thanks to “dream teams” that could defeat it. And yet here we are. With no actual cure in sight.

It was not for lack of trying. There have been billions of dollars spent on fighting cancer. There are more non-profit groups dedicated to stopping cancer than heart disease, AIDS, Alzheimer’s and stroke combined.

But for all of that well-intended passion, the failure rate of clinical trials highlighting new cancer treatments hovers between 91 and 97 percent. So a lot of people are losing this battle. And the breakthrough “dream teams” just aren’t delivering what they’ve promised.1

So what has happened?

It turns out that cancer is more complex and able to go into hiding, even after initial treatment, and then return than we ever imagined. And it’s due, in a large part, to cancer stem cells, something that leading edge research—especially research involving botanical medicines—is discovering more about every day. But will knowing this make it easier for patients and practitioners? The answer is: it very well could.

What Current Cancer Treatment Does—and Doesn’t—Do

Most treatments for cancer consist of what could be called a “cut, burn and poison” methodology. And about half of the time, it works. The usual order of events is surgery, followed by radiation or chemotherapy drugs. Childhood leukemia responds pretty well to chemotherapy, but other cancers like melanoma, thyroid cancer or esophageal cancer show very little benefit.

Plus, as everyone knows, the damage from radiation and chemo drugs causes intensive damage and can be quite literally, a killer. Those who survive the suffering that accompanies that treatment are still left with a great risk of recurring cancer.

And the unfortunate truth is, patients rarely die from the original cancer. They die from metastasis that occurs before the conventional treatment has even started, immunosuppression because of the toxic nature of chemotherapy or radiation treatment, or from cancer recurrence.2

In fact, one of the most significant risk factors for cancer is having had cancer already. In these cases, patients are left vulnerable to recurrence, even after they get an “all clear” signal. Cancer stem cells may be one of the reasons why. Much in the way that the over-prescription of antibiotics has left people susceptible to resistant bacterial infection, current cancer treatments can acculturate remaining cancer cells to be more resilient and to return even stronger than before.3-5

Cancer Stem Cells: The Reason for Recurring Tumors?

A traditional view of the development of cancer is that over time, healthy cells are affected by a series of small mutations that ultimately develop into tumors. These cells’ normal life cycle mechanisms are essentially erased from their original programming. With no self-controlling system in place, there’s nothing to tell these cells to stop replicating, and a tumor is born.6

But another model of cancer—the cancer stem cell model—points to a small group of cells that may be responsible for a majority of cases.

Cancer stem cells are like a dark mirror version of normal stem cells, and share many of the same characteristics. For example, cancer stem cells are able to self-renew, so just like normal stem cells, they can reproduce themselves. Cancer stem cells can also differentiate into a number of different types of cancer, including breast cancer, colon cancer, melanoma, brain tumors and lung cancer; so like normal stem cells, they can essentially create whatever they choose. And cancer stem cells use common signaling pathways to accomplish their tasks, traveling easily throughout the body, and setting up shop wherever they’d like. And this makes them especially difficult to track down.7

Botanicals That Improve Chemotherapy and Battle Cancer Stem Cells

There are ways that practitioners can help even the odds. Leading research with specific botanicals have seen some truly incredible results. In some cases, these herbs and their active compounds can make conventional treatment more effective at lower doses, and spare the patient increased suffering and risk from high dosages of chemotherapy drugs or radiation. In other cases, these botanicals directly pursue and eliminate cancer stem cells while not causing harm to healthy cells. And each of them are easily incorporated into your practice.

Curcumin From Turmeric

I’m sure that many practitioners and their patients are already familiar with curcumin from turmeric (Curcuma longa), especially for its pain-relieving ability to inhibit COX-2 activity.

Curcumin from turmeric has been a natural medicine for centuries, as a powerful anti-inflammatory and antioxidant, and most recently in anti-cancer research. Curcumin stops the formation, growth and spread of cancer, and works through multiple pathways in the body, modulating transcription factors, inflammatory cytokines, growth factors and enzymes involved in tumor formation. It has a wide scope and can focus on at 100 molecular targets at once, so curcumin provides exactly the kind of resourcefulness that’s needed to fight cancer.8

Not surprisingly, there are more than 5,000 studies about curcumin and cancer alone, and more work being done all the time.

One way for curcumin to be used in integrative practice is as an adjunct therapy for patients undergoing chemotherapy. Curcumin has been shown to sensitize colorectal cancer cells that would otherwise require massive doses of drugs to eradicate (dangerous, possibly even fatal, for the patient) or that would escape the effects of chemotherapy (with the likely potential of cancer recurrence.)

According to the Centers for Disease Control and Prevention (CDC), colorectal cancer is the third leading cause of cancer deaths in the United States.9 Recurrence in colorectal cancer can be as high as 50 to 60 percent. In fact, some tumor cells can become so resistant to chemotherapy that they survive even with more than 100 times the toxic dose of the drugs. Because this isn’t workable in practice, recurrence is a major cause of mortality in colorectal cancer patients. Fortunately, scientific research with curcumin shows that it may help reverse this direction.10

Curcumin used in conjunction with 5-fluorouracil (5-FU) enhanced the sensitivity resistant human colon cancer cells to the effects of 5-FU. The combination also showed higher levels of apoptosis than either used alone, and it inhibited proliferation in both the parental and 5-FU resistant colorectal cancer cells.11

In other research, curcumin has inhibited dangerous attributes of chemotherapy drugs. For instance, paclitaxel (Taxol) among others, is a chemotherapy medication used to treat a number of types of cancer. This includes ovarian cancer, breast cancer, lung cancer, Kaposi sarcoma, cervical cancer and pancreatic cancer. But this medicine also activates nuclear factor kappa B (NF-kappa B), which has the opposite intended effect of potentially enhancing metastasis and cancer cell survival. However, since curcumin inhibits the activity of NF-kappa B, it was found to enhance the anti-tumor activity of paclitaxel in vitro and in vivo, ultimately inhibiting lung metastasis of human breast cancer cells.12

Additionally, curcumin has been shown in clinical research to alleviate side effects of one of the most common treatments for prostate cancer, external beam radiotherapy (EBRT). This form of prostate cancer therapy is often accompanied by sexual dysfunction, digestive problems and urinary tract issues.

In one study, researchers tested the ability of curcumin to prevent the side effects of ERBT treatment in men with prostate cancer. Patients took three grams of curcumin (two 500 mg capsules, three times daily) or a placebo beginning one week before radiotherapy until the completion of the treatment. Each curcumin capsule contained a full spectrum of curcuminoids: curcumin, desmethoxycurcumin, bisdemethoxycurcumin and essential oil of turmeric.

By the end of the 20-week period, there was a difference between the curcumin group and the placebo group was in urinary symptoms. The curcumin group saw a 50 percent difference in the frequency of daytime urinations, a 20 percent reduction in sleep disturbances at night in order to urinate and a 15 percent reduction in problems with urinary leakage.13

A second similar clinical study found that while prostate-specific antigen levels dropped in both the curcumin and placebo groups, only the curcumin group saw a higher total antioxidant capacity. Curcumin may preserve the body’s own defenses in the midst of cancer and radiation treatment.14

Curcumin also has an inhibiting effect on cancer stem cells. One study adding curcumin (BCM-95) to metformin (which shows chemopreventive activity in cases of oral cancer), found that the combination decreased tumor volume compared to controls, and improved the survival rate of the animals in the study. But beyond this, the researchers also found that this treatment stopped the self-renewal and metastasis of cancer stem cells through downregulation of markers CD44 and CD133.15

Pancreatic cancer is incredibly aggressive. It is the fourth leading cause of cancer-related death in the United States. Gemcitabine is a chemotherapy drug used to treat cancer of the bladder, ovary, breast and pancreas, among others. But, cancer cells, specifically cancer stem cells, acquire a resistance to this drug.

In cell research, curcumin (BCM-95) prevented the formation of spheroids, cellular aggregates that cancer stem cells use to survive, inhibited gemcitabine-resistant tumor growth and resensitized the resistant pancreatic cancer cells to the drug.16

Other work has found that curcumin suppresses cancer stem cells in lung cancer and bladder cancer, via the Sonic Hedgehog (Shh) pathways, decreasing their markers and proliferation, and inducing apoptosis.17,18

Grape Seed Extract OPCs

Oligomeric proanthocyanidins (OPCs) can prevent the formation, growth and spread of tumor cells. And like curcumin, OPCs from grape seed have also been shown to bolster the effectiveness of the chemotherapy drug 5-FU for killing colon cancer cells—in one case by 26 percent. The grape seed extract improved cell cycle arrest and inhibited transporter pathways.

Here again, like curcumin, this means that grape seed extract could be part of an adjunct therapy to chemotherapy in patients with colorectal cancer and make those drugs more effective at lower dosages.19

Grape seed’s activity against cancer stem cells, tumor development and cancer cell signaling are making this botanical a powerful ally in any patient’s treatment plan. Recent discoveries have found that OPCs work along key pathways, including Hippo-YAP.

The Hippo-YAP pathway is necessary for cancer stem cell survival. Researchers found that OPCs from grape seed suppress this pathway, and can arrest the cancer cell life cycle, halt tumors in their growth phase, and target specific microRNAs that reduce cell proliferation and induce apoptosis.

OPCs from the specific tannin-free grape seed suppressed spheroid derived cancer stem cell formation and decreased the expression markers including LGR5, CD44 and CD133. These components also upregulated tumor suppressor miRNAs miR-34a and miR-200c.20

Grape seed OPCs were so effective that researchers concluded, “While the efficacy of these botanicals is relatively moderate compared to chemotherapeutic drugs, their low toxicity, cost-effectiveness and other health benefits make them attractive supplements for both cancer prevention and treatment.”

Other research on OPCs from grape seed extract has found similar results on cancer stem cells and tumor growth. In some cases, there were dramatic changes on tumor size.

Further, in vivo study tests found additional results that are quite pertinent to integrative practice. Researchers compared tannin-free OPCs from a French grape seed extract (VX1) to a standard tannin OPC unfractionated grape seed extract. The low molecular weight tannin-free botanical ingredient was much more effective—even at low dosage levels. In just 13 days, 100 mg of OPCs reduced tumor size by 65 percent. Even at 50 mg—half the dosage—these OPCs reduced tumor size by 40 percent. Compared to standard grape seed extract at only 13 percent and 8 percent, respectively, it shows what an incredible difference the form of an ingredient can make. Additionally, there were no harmful effects on healthy cells—these actions were targeted to cancer cells only.21

Another scientific study combined curcumin (BCM-95) and OPCs from French grape seed (VX1) to see how the two worked together.

Researchers found that when the two were combined, the anti-cancer effects are better than either used alone. For example, curcumin alone produced a 28 percent reduction in tumor volume; OPCs produced a 43 percent reduction in tumor volume, but the two together reduced tumor volume by 57 percent. As each botanical works along different pathways, with one being fat-soluble, and the latter being water soluble they could be recommended in tandem for patients, without being a burdensome regimen.22

Other Botanicals: Andrographis, Boswellia and Ginseng

Andrographis

Like any botanical, andrographis (Andrographis paniculata) contains a wealth of valuable compounds. One in particular, andrographolide, has been the subject of the most studies.

Regarding cancer, andrographolide from andrographis has been shown to stop the growth and proliferation of melanoma cells, stopped the growth and formation of pancreatic tumor cells, and suppressed the ability of glioblastoma multiform cells to migrate.23-26

Andrographolide has also been shown to inhibit stem cell characteristics of oral carcinomas and reduce tumor growth, by increasing miR-218 activation. Researchers concluded that andrographolide could become a valuable natural compound to treat stem cells that can lead to oral cancer.27

Boswellia

Boswellia (Boswellia serrata) may be better known as frankincense to many of your patients. One of the unique attributes of this herb is that it fights 5-LOX inflammation, making it extremely valuable for individuals with autoimmune diseases, respiratory illnesses and joint pain. It’s also a powerful cancer fighter.

Most studies attribute boswellia’s best qualities to a compound called acetyl-11-keto-beta-boswellic acid, or AKBA. This naturally occurring pentacyclic triterpene is isolated from the gum resin exudate from the stem of the tree.

AKBA has been shown to inhibit tumor growth in colorectal cells by waking up sleeping genes that naturally suppress cancer development.28

Other work has compared boswellia to doxorubicin and 5-fluoroucil for its efficacy in stopping colon and liver cancer cells. And AKBA from boswellia has been shown to slow the growth of leukemia and prostate cancer cells by suppressing angiogenesis.29, 30

Regarding specific stem cell work, AKBA from boswellia inhibited proliferation of docetaxel-resistant prostate cancer cells by blocking their signaling pathways (Akt and Stat3).31

Red Ginseng

Red ginseng (Panax ginseng) has been established as an herbal adaptogen in traditional practice for centuries. Its effects on cancer cells, however, are only beginning to be explored. Emerging studies in just the past year have shown that red ginseng may be another strong ally in the fight against resistant cancer stem cells.

It can reverse chemotherapy resistance in colon cancer cells treated with oxaliplatin, improve the actions of cyclophosphamide, protect the liver from damage induced by the chemotherapy drug Cisplatin, and inhibit the angiogenetic ability of melanoma cancer cells.32-35

While red ginseng contains a variety of helpful compounds, the most studied are ginsenosides. Within that, there is a subgroup called noble ginsenosides, which are absorbable, active and rare in most supplemental forms. Some of the research I’ve cited here zeroed in on Rh2 and Rg3, two noble ginsenosides that appear inhibit the actions of cancer stem cells.

There is a Place for Botanical Treatment of Cancer in Your Practice

As practitioners, I believe we should always emphasize the importance of diet and lifestyle for cancer prevention. But of course, cancer can strike regardless of anyone’s best efforts. Nonetheless, there are interventions with natural medicine which may help stop cancer recurrence by targeting cancer stem cells. There are many factors that lead to the development of cancer in your patients, and each set of conditions is as unique as the individual. As practitioners, assisting patients in a holistic way by arming them with the best that botanicals and science can offer is simply one of our responsibilities. And I believe that there is great hope—and great reason—in doing so.

References:

1 Chi Heem Wong, Kien Wei Siah, Andrew W Lo, Estimation of clinical trial success rates and related parameters, Biostatistics, Volume 20, Issue 2, April 2019, Pages 273–286, https://doi.org/10.1093/biostatistics/kxx069. https://academic.oup.com/biostatistics/article/20/2/273/4817524.

2 Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):1,559–64.

3 “The Stem Cell Theory of Cancer.” Stanford Medicine, Ludwig Center for Cancer Stem Cell Research and Medicine. Available at: Med.Stanford.edu/ludwigcenter/overview/theory.html. Accessed: August 14, 2020.

4 Graeber, C. A cure for cancer: how to kill a killer. The Guardian (online). Sun 4 Nov 2018 03.00 EST Last modified on Wed 14 Nov 2018 05.59 EST Available at: www.theguardian.com/science/2018/nov/04/a-cure-for-cancer-how-to-kill-a-killer-revolutionary-immune-system-immunotherapy. Accessed: August 13, 2020.

5 Treatment—Chemotherapy. Pitt Lecture Series. Available at: http://www.pitt.edu/~super1/lecture/lec0701/l24.htm. Accessed: August 13, 2020.

6 Peiris-Pagès M, Martinez-Outschoorn UE, Pestell RG, Sotgia F, Lisanti MP. Cancer stem cell metabolism. Breast Cancer Res. 2016 May 24;18(1):55.

7 Dawood S, Austin L, Cristofanilli M. Cancer stem cells: implications for cancer therapy. Oncology (Williston Park). 2014 Dec;28(12):1101-7, 1110.

8 Giodano A, Tommonaro, G. Curcumin and Cancer. Nutrients. 2019, 11(10), 2376; https://doi.org/10.3390/nu11102376.

9 “Colorectal Cancer Statistics.” Centers for Disease Control and Prevention (CDC) web site. Available at: https://www.cdc.gov/cancer/colorectal/statistics/index.htm. Accessed: August 14, 2020.

10 Shakibaei M, Buhrmann C, Kraehe P, Shayan P, Lueders C, Goel A. Curcumin chemosensitizes 5-fluorouracil resistant MMR-deficient human colon cancer cells in high density cultures. PLoS One. 2014;9(1):e85397.

11 Toden S, Okugawa Y, Jascur T, et al. Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis. 2015;36(3):355-367. doi:10.1093/carcin/bgv006.

12 Kang HJ, Lee SH, Price JE, Kim LS. Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB in breast cancer cells and potentiates the growth inhibitory effect of paclitaxel in a breast cancer nude mice model. Breast J. 2009;15(3):223-229.

13 Hejazi J, Rastmanesh R, Taleban FA, Molana SH, Ehtejab G. A Pilot Clinical Trial of Radioprotective Effects of Curcumin Supplementation in Patients with Prostate Cancer. J Cancer Sci Ther. 2013;5:320-324.

14 Hejazi J, Rastmanesh R, Taleban FA, Molana SH, Hejazi E, Ehtejab G, Hara N. Effect of Curcumin Supplementation During Radiotherapy on Oxidative Status of Patients with Prostate Cancer: A Double Blinded, Randomized, Placebo-Controlled Study. Nutrition and Cancer. 2016;0(0):1-9.].

15 Siddappa G, Kulsum S, Ravindra DR, et al. Curcumin and metformin-mediated chemoprevention of oral cancer is associated with inhibition of cancer stem cells. Mol Carcinog. 2017;56(11):2446-2460. doi:10.1002/mc.22692.

16 Yoshida K, Toden S, Ravindranathan P, Han H, Goel A. Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression. Carcinogenesis. 2017;38(10):1036-1046. doi:10.1093/carcin/bgx065.

17 Zhu JY, Yang X, Chen Y, et al. Curcumin Suppresses Lung Cancer Stem Cells via Inhibiting Wnt/β-catenin and Sonic Hedgehog Pathways. Phytother Res. 2017 Apr;31(4):680-688.

18 Wang D, Kong X, Li Y, et al. Curcumin inhibits bladder cancer stem cells by suppressing Sonic Hedgehog pathway. Biochem Biophys Res Commun. 2017 Nov 4;493(1):521-527.

19 Ravindranathan P, Pasham D, Goel A. Oligomeric proanthocyanidins (OPCs) from grape seed extract suppress the activity of ABC transporters in overcoming chemoresistance in colorectal cancer cells. Carcinogenesis. 2018 Dec 29.

20 Toden S, Ravindranathan P, Gu J, Cardenas J, Yuchang M, Goel A. Oligomeric proanthocyanidins (OPCs) target cancer stem-like cells and suppress tumor organoid formation in colorectal cancer. Sci Rep. 2018 Feb 20;8(1):3335.

21 Ravindranathan P, Pasham D, Balaji U, Cardenas J, Gu J, Toden S, Goel A. Mechanistic insights into anticancer properties of oligomeric proanthocyanidins from grape seeds in colorectal cancer. Carcinogenesis. 2018 May 28;39(6):767-777.

22 Ravindranathan P, Pasham D, Balaji U, Cardenas J, Gu J, Toden S, Goel A. A combination of curcumin and oligomeric proanthocyanidins offer superior anti-tumorigenic properties in colorectal cancer. Sci Rep. 2018 Sep 14;8(1):13869.

23 Liu G, Chu H. Andrographolide inhibits proliferation and induces cell cycle arrest and apoptosis in human melanoma cells. Oncol Lett. 2018 Apr;15(4):5301-5305. doi: 10.3892/ol.2018.7941. Epub 2018 Feb 2.

24 Bao GQ, Shen BY, Pan CP, Zhang YJ, Shi MM, Peng CH. Andrographolide causes apoptosis via inactivation of STAT3 and Akt and potentiates antitumor activity of gemcitabine in pancreatic cancer. Toxicol Lett. 2013 Sep 12;222(1):23-35.

25 Yang SL, Kuo FH, Chen PN, et al. Andrographolide suppresses the migratory ability of human glioblastoma multiforme cells by targeting ERK1/2-mediated matrix metalloproteinase-2 expression. Oncotarget. 2017 Nov 11;8(62):105860-105872.

26 Islam MT, Ali ES, Uddin SJ, et al. Andrographolide, a diterpene lactone from Andrographis paniculata and its therapeutic promises in cancer. Cancer Lett. 2018 Apr 28;420:129-145.

27 Yang PY, Hsieh PL, Wang TH, et al. Andrographolide impedes cancer stemness and enhances radio-sensitivity in oral carcinomas via miR-218 activation. Oncotarget. 2017;8(3):4196-4207. doi:10.18632/oncotarget.13755.

28 Goel, A. Boswellia extracts induce DNA methylation changes in colon cancer cells. Poster presentation, International Meeting of American Gastroenterological Association, Chicago, IL, May 6 -1 0, 2011.

29 Hamidpour R, Hamidpour S, Hamidpour M, Shahlari M. Frankincense (rǔ xiāng; boswellia species): from the selection of traditional applications to the novel phytotherapy for the prevention and treatment of serious diseases. J Tradit Complement Med. 2013 Oct;3(4):221-6. doi: 10.4103/2225-4110.119723.

30 Alam M, Khan H, Samiullah L, Siddique KM. A review on phytochemical and pharmacological studies of Kundur (Boswellia Serrata Roxb Ex Colebr.)-A Unani drug. J Appl Pharm Sci. 2012;2:148–56.

31 Liu YQ, Wang SK, Xu QQ, Yuan HQ, et al. Acetyl-11-keto-β-boswellic acid suppresses docetaxel-resistant prostate cancer cells in vitro and in vivo by blocking Akt and Stat3 signaling, thus suppressing chemoresistant stem cell-like properties. Acta Pharmacol Sin. 2019 May;40(5):689-698.

32 Ma J, et al. Reversal effect of ginsenoside Rh2 on oxaliplatin-resistant colon cancer cells and its mechanism. Exp Ther Med. 2019 Jul;18(1):630-636. 33 Liu X et al. Ginsenoside Rg3 improves cyclophosphamide-induced immunocompetence in Balb/c mice. Int Immunopharmacol. 2019 Jul;72:98-111.

34 Alrashed AA, El-Kordy EA. Possible Protective Role of Panax Ginseng on Cisplatin-Induced Hepatotoxicity in Adult Male Albino Rats (Biochemical and Histological Study). J Microsc Ultrastruct. 2019 Apr-Jun;7(2):84-90.

35 Meng L, et al. Antitumor activity of ginsenoside Rg3 in melanoma through downregulation of the ERK and Akt pathways. Int J Oncol. 2019 Jun;54(6):2069-2079.

Dr. Holly Lucille is a nationally recognized licensed naturopathic physician, lecturer, educator and author of Creating and Maintaining Balance: A Women’s Guide to Safe, Natural, Hormone Health. Her private practice, Healing From Within Healthcare, focuses on comprehensive naturopathic medicine and individualized care. Outside of her practice, Dr. Lucille holds a position on the American Association of Naturopathic Physicians board of directors and is on the faculty of the Global Medicine Education Foundation. She is the past president of the California Naturopathic Doctors Association, where she spearheaded a lobbying effort to have naturopathic doctors licensed in the state of California. A graduate from the Southwest College of Naturopathic Medicine, Dr. Lucille’s commitment to naturopathic medicine has been recognized with the Daphne Blayden Award and, more recently, the SCNM Legacy Award.