Acute myeloid leukemia (AML) is an aggressive, rapidly fatal blood cancer. Treatment modalities exist, but the complete remission rate during induction therapy is only 60-80% in young adults and decreases as patients age or if they suffer from other comorbidities. New treatment modalities are needed to overcome chemoresistance and to improve morbidity and mortality.
Cannabidiol (CBD), with growing evidence to support its role in cancer treatment, is a potentially safe and promising adjunctive therapy for the treatment of AML. Preclinical data suggests that the combination of CBD with conventional AML therapy can lead to enhanced anticancer activity through the modification of key signaling pathways. However, further research and clinical trials are necessary to determine the exact signaling pathways impacted by CBD, the optimal combination of cannabinoids needed to elicit antineoplastic responses, and the ideal sequencing of the cannabinoids and chemotherapy to induce apoptosis of AML cell lines. Further, large scale clinical trials are necessary to achieve these results.
Myeloblasts with Auer rods characteristic of AML (Image Credit: Paulo Henrique Orlandi Mourao).
Cannabidiol (CBD) as an Adjunct to Standard of Care Treatment
Cannabinoids are a group of chemicals extracted from the cannabis plant. There is a growing body of research pointing toward the therapeutic potential of cannabinoids, especially CBD, in cancer treatment.
The anticancer effect seems to stem, in part, from activation of cannabinoid receptors on tumor cells. Activation of these receptors slows cancer cell growth, induces apoptosis, and inhibits neovascularization of tumors (Liu, Lett Drug Disc Des, 2006).
The CB2 receptor has previously been shown to be overexpressed in several AML lines (Jordà, Blood, 2004), making it a potential target for CBD therapy. One group of researchers was able to demonstrate that CBD exposure to leukemia cells led to significant CB2 receptor-mediated decrease in the number of viable cells as well as the induction of apoptosis, both in vitro and in vivo (McKallip, Mol Pharmacol, 2006).
However, the impact of cannabinoids does not appear to be limited to receptor responses alone. Cannabinoids appear to elicit cell-killing mechanisms even when the cannabinoid receptors are not present on target cells. In fact, anticancer activity, independent of cannabinoid receptors, has been seen in several leukemia cell types treated with cannabinoids (Powles, Blood, 2005). This receptor-independent anticancer activity is presumed to be due to the ability of cannabinoids to disrupt intracellular signaling pathways. (Liu, Curr Clin Pharm, 2010).
While there have been demonstrated benefits to the use of CBD as a monotherapy, recent research suggests that combination therapy with other chemotherapeutic drugs may be more advantageous, by targeting progression of the cancer at different levels and minimizing toxicities of these therapies relative to higher doses when used as monotherapies (Yasmin-Karim, Front Oncol, 2018).
For example, in one recent in vitro study by Scott, et al, researchers found that when cannabinoid monotherapy was used on cell lines of acute lymphocytic leukemia and promyelocytic leukemia (a subtype of AML), there was reduction in neoplastic cell counts by stopping the growth of the malignant cells through cytostatic mechanisms. However, when cannabinoids were combined, outcomes were improved when compared to any one compound alone (Scott, Anticancer Res, 2013).
Another in vitro study demonstrated that the combination of cannabinoids with anti-leukemia drugs, especially cytarabine and vincristine, actually increased the rate of cancer cell apoptosis, instead of just halting its growth (Scott, Int J Onc, 2017). Given that cytarabine is the most common chemotherapy used for the treatment of AML, cannabinoids could potentially be used as effective treatment adjuvants, especially in patients demonstrating resistance to treatment.