Go Green to Go Pink: Cannabis as Treatment for Breast Cancer

October is Breast Cancer Awareness Month in the United States.  Approximately 1 in 8 U.S. women and 1 in 1000 U.S. men will be diagnosed with invasive breast cancer within their lifetime.  In 2016, 249,260 new cases of invasive breast cancer are expected to be diagnosed.  Although great strides have been made in the treatment of breast cancer, an estimated 41,000 people each year die from breast cancer in the U.S. Because breast cancers can develop resistance to chemotherapy medications, researchers are continually looking for new compounds to treat breast cancer.  Originally only used to treat the effects of chemotherapy, cannabis and cannabinoids have recently emerged as a potential therapeutic target.  Let’s review the available evidence for the use of cannabinoids as a medication to treat breast cancer.

Breast cancer originates as a mutation in breast tissue cells.  This mutation leads to the production of various substances that are designed to encourage the growth and consolidation of tumor cells, as well as the spread of cancer cells throughout the body (metastasis).  Because metastasis of breast cancer is responsible for up to 90% of deaths, researchers have focused their efforts on finding substances that have the ability to decrease metastasis and shrink tumors.  Investigators have focused on three cannabinoid substances as possible treatment targets: cannabidiolic acid (CBDa), cannabidiol (CBD), and delta-9 tetrahydrocannabinol (THC).

Cannabidiolic acid is one of four cannabinoids formed from the breakdown of cannabigerolic acid (CBG).  It is converted to CBD by exposure to heat and/or light, in a process called decarboxylation.  Cannabidiolic acid is believed to have anti-nausea and anti-inflammatory properties.  It is believed to fight cancer in two main ways: by decreasing migration of highly invasive cancer cells, and by decreasing blood and nutrient supply to the tumor.

To test the first theory, that CBDa decreases migration of highly invasive cancer cells, molecular biologists from the Daiichi University of Pharmacy in Japan prepared and then exposed a strain of highly-invasive breast cancer cells to three different concentrations of CBDa for 12 hours within their experimental laboratory. They also exposed another group of the same cell strain to a low concentration of CBD for 12 hours, to distinguish whether the results were due to CBDa or the conversion of CBDa to CBD.  They compared these four treatment groups to a control treatment without any cannabinoids.  Cells exposed to low and medium concentrations of CBDa showed a decreased percentage of cells migrating to other sites relative to the control treatment, and cells exposed to a high concentration of CBDa showed virtually no migration.  However, cells exposed to low concentrations of CBD actually showed increased migration relative to the control group, showing that CBDa, and not CBD, was responsible for the decreased migration of invasive cells.

Building upon that study, the same  molecular biologists from the Daiichi University of Pharmacy looked more closely at the mechanisms underlying the decreased migration of invasive cancer cells.  They observed the same type of highly invasive breast cancer cells as in the previous study, selecting those that produced a high amount of a substance called cyclooxygenase-2 (COX-2).  COX-2 is an enzyme that increases the production of inflammatory substances such as prostaglandins, as well as increasing the construction of blood supply to the tumor and increasing the production of id-1, a molecule that works to increase movement of invasive cancer cells to other sites.  Researchers then took those high COX-2 producing cells and exposed them to a single high concentration of CBDa for 48 hours, observing enzyme and substance activity in real time.

Researchers discovered that cells exposed to CBDa decreased the manufacture of COX-2 and id-1, while increasing the production of SHARP-1, which suppresses breast cancer metastasis.  These results show promise for CBDa to not only reduce metastasis of breast cancer, but also to shrink tumors by starving them of blood, and therefore oxygen and nutrients.

Cannabidiol also plays a role in fighting breast cancer.  CBD decreases the production of id-1, which regulates the mobility of invasive cancer cells.  CBD also induces programmed cell death (self-destruct) of breast cancer cells, and mobilizes the body’s own immune system to destroy cancer cells.

Researchers at Beth Israel Deaconess Medical Center in Boston took  samples from 5 different human breast cancer cell lines.  In addition to a control (no CBD),  researchers exposed cells from each cell line to either 2.5, 5, 7.5, or 10 micromolar concentrations of CBD for 24 hours.  They measured the percentage of breast cancer cells that survived and the percentage of programmed cell death in each group.   As breast cancer cells were exposed to increasing concentrations of CBD, percentage of breast cancer cell survival declined and percentage of programmed cell death increased.   Researchers also compared the percentage of programmed cell death between an aggressive breast cancer cell line and a non-tumor human cell line after both were exposed to various concentrations of CBD for 24 hours.  Breast cancer cells showed a higher percentage of programmed cell death than non-tumor cells, showing that CBD preferentially targets tumor cells over healthy cells.

Researchers at the California Pacific Medical Center in San Francisco took the findings discovered in research with CBD on breast cancer cells in vitro (in the lab) and sought to determine if they could also apply in vivo (within the body).  They injected laboratory mice with invasive breast cancer cells,,then separated them into 3 treatment groups: control (no CBD), low dose CBD, and high dose CBD.  Investigators injected the mice with either placebo, 1 mg/kg CBD, or 5 mg/kg CBD, then measured tumor size and number of metastatic sites daily.  Mice injected with CBD, but not control injections, showed decreased tumor size at day 18 and peaked at 22-24 days.  However, tumor cells started to become resistant to CBD at day 25, and by the end of the study, showed no difference compared to control.  What differed between the groups, and maintained through the end of the study, was the number of metastatic sites, with the 5 mg/kg group having the fewest metastatic sites: 10 in the 5 mg/kg group compared to 26 in the control group.   In addition, the metastatic tumors in the CBD-treated group were smaller, on average, than the control group.  While these experimental tumors may have become resistant to CBD (due to mutations in the breast cancer cells), their spread was clearly impaired by the presence of CBD.

THC also has a role in treating breast cancer.  THC has long had a role in treating the symptoms of breast cancer and the side effects of chemotherapy treatment, such as nausea and lack of appetite.   In treating breast cancer, previous studies have shown that THC has anti-estrogen properties and inhibits the proliferation of breast cancer by encouraging programmed cell death.

In a 2013 study, researchers exposed 2 types of human breast cancer cell lines to 6 different concentrations of THC, as well as to a control solution without THC, for 48 hours.  They discovered that as the concentration of THC increased, the percentage of cells surviving decreased relative to the control group.  Researchers then gathered another sample of the same cell lines and split them into four treatment groups: control, exposure to THC, exposure to E2 (an estrogen signaler to increase tumor proliferation), and exposure to a combination of THC and E2. They found that when THC was present, even when estrogen signaling was boosted, fewer breast cancer cells survived.  Since most breast cancers are estrogen dependent, decreasing estrogen-based signalers would lead to decreased tumor growth and increased programmed cell death.

While the data looks promising for the use of cannabis to treat breast cancer, a few studies have shown a paradoxical increase in tumor size in the presence of THC.  These studies examined THC and other cannabinoids in the presence of human breast cancer cell lines that had low numbers of cannabinoid receptors.  With fewer receptors, there were fewer sites for the cannabinoids to work.  Breast cancer can be caused by a number of different cell lines, and can develop resistance to treatment, which can make it challenging to treat.

Another large drawback to these studies is the lack of published data in humans.  These studies either looked at cannabinoids interacting with cells in a lab, or in lab mice artificially exposed to breast cancer.  Both situations control much of the experimental environment, including selecting for pure CBDa, CBD, or THC.  However, treating humans in an uncontrolled environment for breast cancer (which is already quite variable),  with cannabis or cannabis products that are produced by humans, can lead to a wide variability in results.  Further research needs to expand its subjects into lab animals genetically closer to humans, then into real world human case reports and small studies, all the way up to randomized, controlled trials in humans.  While the current data looks positive, it is merely a base upon which to expand our knowledge about how cannabis works in the body, especially in the setting of breast cancer.

References:

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