Mazuz M., Tiroler A.s, Moyal L., Hodak E., Rajan S.N., Vinayaka A.C., Gorovitz-Haris B., Lubin I., Drori A., Drori G., Van Cauwenberghe O., Faigenboim A., Namdar D., Amitay-Laish I., Koltai H. (2020)

Synergistic cytotoxic activity of cannabinoids from Cannabis sativa against Cutaneous T Cell Lymphoma (CTCL) in-vitro and ex-vivo.

Oncotarget, 11:1141-1156.

Cannabis sativa produces hundreds of phytocannabinoids and terpenes. Mycosis
fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL),
characterized by patches, plaques and tumors. Sézary is a leukemic stage of CTCL
presenting with erythroderma and the presence of neoplastic Sézary T-cells in
peripheral blood. This study aimed to identify active compounds from whole cannabis
extracts and their synergistic mixtures, and to assess respective cytotoxic activity
against CTCL cells. Ethanol extracts of C. sativa were analyzed by high-performance
liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GC/MS).
Cytotoxic activity was determined using the XTT assay on My-La and HuT-78 cell lines
as well as peripheral blood lymphocytes from Sézary patients (SPBL). Annexin V assay
and fluorescence-activated cell sorting (FACS) were used to determine apoptosis
and cell cycle. RNA sequencing and quantitative PCR were used to determine gene
expression. Active cannabis compounds presenting high cytotoxic activity on My-La
and HuT-78 cell lines were identified in crude extract fractions designated S4 and S5,
and their synergistic mixture was specified. This mixture induced cell cycle arrest and
cell apoptosis; a relatively selective apoptosis was also recorded on the malignant
CD4+CD26- SPBL cells. Significant cytotoxic activity of the corresponding mixture of
pure phytocannabinoids further verified genuine interaction between S4 and S5. The
gene expression profile was distinct in My-La and HuT-78 cells treated with the S4
and S5 synergistic mixture. We suggest that specifying formulations of synergistic
active cannabis compounds and unraveling their modes of action may lead to new
cannabis-based therapies.

Koltai H. and Namdar D. (2020)

Cannabis phytomolecule 'entourage': from domestication to medical use.

Trends in Plant Sciences, in press

Highlights

 

  • Cannabis has been used for millennia by humanity for social, ritual, and medical purposes. Humans bred and selected for cannabis strains based on their needs.

  • Today, patients are treated by cannabis ‘strains’, without a clear definition of activity or known chemical content.

  • Cannabis sativa strain taxonomy is based on the content of two phytocannabinoids only, Δ9-tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA).

  • C. sativa produces hundreds of phytomolecules, including phytocannabinoids, terpenes, and flavonoids.

  • Some cannabis phytomolecules interact, causing enhanced biological activity. Defining this phenomenon, known as the ‘entourage effect’, is one of the leading challenges in the field of research.

Koltai H, Poulin P, Namdar D. Promoting cannabis products to pharmaceutical drugs. European Journal of Pharmaceutical Sciences. 2019 Apr 30;132:118-20.

Cannabis sativa is widely used for medical purposes. However, to date, aroma, popular strain name or the content of two phytocannabinoids—Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are mostly considered for therapeuticactivity. This is despite the hundreds of compounds in this plant and their potential synergistic interactions inmixtures. New, specific and effective cannabis-based drugs must be developed to achieve adequate medical standards for the use of cannabis. To do this, the comprehensive molecular profile of cannabis-based drugs must be defined, and mixtures of compounds should be tested for superior therapeutic activity due to synergistic effects compared to individually isolated cannabis compounds. The biological pathways targeted by these new drugs should also be characterized more accurately. For drug development and design, absorption, distribution, metabolism and elimination versus toxicity (ADME/Tox) must be characterized, and therapeutic doses identified. Promoting the qualityand therapeutic activity of herbal or synthetic cannabis products to pharma grade is a pressing need worldwide.

Namdar D, Voet H, Ajjampura V, Nadarajan S, Mayzlish-Gati E, Mazuz M, Shalev N, Koltai H. Terpenoids and Phytocannabinoids Co-Produced in Cannabis Sativa Strains Show Specific Interaction for Cell Cytotoxic Activity. Molecules. 2019 Jan;24(17):3031.

Mixtures of different Cannabis sativa phytocannabinoids are more active biologically than single phytocannabinoids. However, cannabis terpenoids as potential instigators of phytocannabinoid activity have not yet been explored in detail. Terpenoid groups were statistically co-related to certain cannabis strains rich in Δ9-tetrahydrocannabinolic acid (THCA) or cannabidiolic acid (CBDA), and their ability to enhance the activity of decarboxylase phytocannabinoids (i.e., THC or CBD) was determined. Analytical HPLC and GC/MS were used to identify and quantify the secondary metabolites in 17 strains of C. sativa, and correlations between cannabinoids and terpenoids in each strain were determined. Column separation was used to separate and collect the compounds, and cell viability assay was used to assess biological activity. We found that in “high THC” or “high CBD” strains, phytocannabinoids are produced alongside certain sets of terpenoids. Only co-related terpenoids enhanced the cytotoxic activity of phytocannabinoids on MDA-MB-231 and HCT-116 cell lines. This was found to be most effective in natural ratios found in extracts of cannabis inflorescence. The correlation in a particular strain between THCA or CBDA and a certain set of terpenoids, and the partial specificity in interaction may have influenced the cultivation of cannabis and may have implications for therapeutic treatments.

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