Cannabis-derived Compounds Exhibit Synergistic Cytotoxic Effects Against Colon Cancer Cells
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Cannabis is known to be a pharmacologically active drug with a broad array of potential applications, such as an antipsychotic or an anti-epileptic medication. Perhaps then it is of no surprise that cannabis research for the creation of effective anti-cancer medicines is an active field. A number of non-psychoactive components of cannabis have indeed been shown to control the proliferation and induce the apoptosis of certain cancer cell types, such as breast, lung, and prostate cancers, by altering the signal pathways needed for cell growth and survival.
Colorectal cancer is the third most common cancer diagnosis, and the fourth most common cause of cancer-related deaths worldwide. This is despite huge advancements in cancer screening and the introduction of novel anti-cancer drugs. Due to the reported effect of some cannabinoids on other cancer cell types, the use of cannabis-based therapeutics for controlling colorectal cancer cells and premalignant precursor adenomatous polyps has become an active avenue of research.
The cytotoxic properties of cannabis extracts
To date, most of the research into cannabis as an anti-cancer drug focuses solely on the properties of tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabigerol (CBG), despite the cannabis plant consisting of over 500 unique chemical compounds. Recognizing this, a group of researchers in Israel recently conducted a study of different cannabis extracts to examine the potential of a wider range of cannabinoids to aid in the creation of effective anti-cancer agents.
The cannabis extracts were created from the flowers of two different cannabis plants, one that was fresh and one that had been heated prior to extraction. These extracts were then separated into fractions using high-performance liquid chromatography (HPLC) and their composition analyzed using gas chromatography coupled with mass spectrometry (GC-MS). The cytotoxicity of each fraction was determined by examining their effect on cell cultures grown for the purpose of the study.
After treating cancerous cell cultures with the extracts overnight, it was found that both had a similar magnitude of cytotoxic effect on the colon cancer cell cultures. This is a preliminary indication that cannabis-based medicines could have a similar effect on colon cancer as already observed in breast, lung, and prostate cancers.
In order for these cannabis extracts to be used medicinally, it is important that healthy colon cells are not attacked to the same extent. When healthy colon cell cultures were examined, those that had been treated with extracts derived from heated flower material were found to have an even more reduced cell viability than the cancerous cells treated by the same extract. Whereas the extracts derived from the fresh flowers were less active on the healthy cells compared to the cancerous cells by a factor of 1.7. Previous research from the same group also focusing on cannabis extracts characterized extracts derived from heated plant material as containing mostly CBD, CBG, and THC. The fresh extracts predominantly contained the acidic forms of these compounds: CBDA, CBGA, and THCA.
The chemical composition of a fresh flower extract
To study the effects of the fresh extracts more closely, the individual fractions of the extract found using HPLC analysis were also tested for cytotoxic behavior. One fraction, containing predominantly THCA, was found to exhibit moderate cytotoxic behavior, but when combined with other fractions cytotoxicity increased. A marked increase was observed when the THCA fraction was combined with another fraction that contained mostly CBGA, despite the CBGA fraction only displaying low levels of cytotoxicity when used in isolation. Importantly, despite the increase in cytotoxicity of the THCA+CBGA combination on cancerous cell lines, it exhibited the same reduced cytotoxicity on healthy cells as seen with the original fresh extract. The cell viability of the different cancer cell cultures after treatment with THCA+CBGA varied between 45-60%, whereas the cell viability of the healthy cell cultures under the same treatment was approximately 80%.
In order to determine whether this increased cytotoxicity is due to a simple additive effect of utilizing multiple cannabinoids at once or a more complex synergistic relationship between the two fractions, the partial effects of the fractions were calculated by applying the Bliss Independence Model across a range of cytotoxicity tests conducted at different concentrations of the two fractions. The Bliss Independence Model is known to have a relatively high risk of returning false-positive results, so to ensure the relationship between the fractions is correctly understood, Combination Index analysis was also carried out. Both of these methods confirmed a synergistic relationship between the THCA and CBGA fractions.
The therapeutic value of THCA+CBGA mixtures
Further study of the THCA+CBGA combination was carried out on biopsy tissues of polyps and normal colon tissues obtained from four consenting patients who had undergone necessary colonoscopies. The effectiveness of the THCA+CBGA fraction mixture varied from patient to patient. In some cases, the THCA+CBGA mixture was more effective than THCA alone, but in the others, it offered no significant improvement over THCA on its own. In three out of the four cases polyp cell viability was reduced, demonstrating effective cytotoxic behavior, but given the small sample size, no statistical conclusions can be drawn from this regarding universal effectiveness.
The method by which the THCA+CBGA mixture works to combat colon cancer and polyp cells was investigated through RNA sequencing. 2283 genes were found to be expressed differently in cells that had been treated with THCA+CBGA compared to those treated with THCA or CBGA alone. The genes affected here include some that control cell cycle G1/S phase transition, the Wnt signaling pathway, and the p53 and apoptosis signaling pathways. The alteration of these pathways is thought to be the cause of the majority of the THCA+CBGA cytotoxicity observed in this study.
Future applications for cytotoxic cannabis extracts
This study has demonstrated the potential for cannabis-based products, specifically extracts derived from fresh cannabis inflorescences, for use as anti-cancer agents. A combination of THCA and CBGA can interact synergistically to cause distinct gene expression, induction of cell cycle arrest, and apoptotic cell death in colon cancer cells. In addition, THCA+CBGA has also shown some activity against adenomatous polyps. This activity, combined with the low cytotoxicity measured against healthy cells, indicates that cannabis-based cancer therapies warrant further investigation.;
Further study is needed to fully characterize the mechanism of action by which THCA+CBGA affects healthy cells as well as cancerous cells and polyps. Additional in vitro and in vivo study of the relationship between THCA and CBGA is also needed to better understand when the two interact additively versus synergistically.