et al. 2016). Thus, this section focuses on the role of cannabinoids in evading

chemoresistance in cancer patients.

12.5.8.1 Cannabinoid Modulators Against Chemotherapy Resistance

in Cancer

In addition to antiproliferative action of endocannabinoid system, studies have also

showed that cannabinoid modulators are equally effective against resistant cancer

cells. The role of THC and CBD has been seen in modulating the expression of

MDR1 in leukemia cells (CEM/VLB100). THC acts through CB1 receptor, while

CBD targets both the receptors and through TRPV-1 channels (Arnold et al. 2012).

Another in vitro study by Holland et al. on leukemic cells showed that cannabinoid

treatment reduces the expression of MDR1 in these cells. It is also illustrated in the

studies that efflux activity does not get altered during this process (Holland et al.

2007, 2008).

Additionally, in glioma cells, THC and CBD synergize the cytotoxicity of

vinblastine and temozolomide (Holland et al. 2006). This finding was also replicated

in vivo (T98G glioma xenograft) when cannabinoids was co-administrated with

temozolomide (TMZ). It was hypothesized that cannabinoids when administered in

combination help in overcoming resistance by stimulating autophagy and thereby

promoting cell death (Torres et al. 2011). Likewise, apoptosis-inducing potential of

cannabinoid agonists was observed to be significantly enhanced by pharmacological

inhibition of well-known cancer-causing oncogenes like EGFR, ERK79, or AKT in

glioma cells.

Xian et al. found out in an in vitro study that treatment of 5-fluorouracil-resistant

gastric cancer cells (SNU-620-5FU/1000) by cannabinoid agonist (WIN 55,212-2)

can induce cytotoxicity. Furthermore, upregulation of cleaved caspase-3 and cleaved

PARP and downmodulation of phospho-ERK1/2, phospho-AKT, BCL2, and BAX

are some observations from this study that are adding to the anticancer effect of

cannabinoids in resistant cancers too (Xian et al. 2013).

Cannabinoid agonists CBD and O-1602 were studied extensively in the amelio-

ration of chemotherapy resistance in paclitaxel-resistant breast cancer cell lines and

also in zebrafish xenograft model. In these models, single-agent treatment with

paclitaxel was not enough in killing the chemo-resistant cancer cells. However,

combination treatment with cannabinoids and paclitaxel was found to be effective

in inducing cell death. Cannabinoids are shown to reduce the viability and metastasis

in MDA-MB-231 cells via apoptosis possibly which is mediated through ROS

activation. Additionally, other GPCRs have also been found to play significant

role in tumor progression and metastasis. In that context, GPR55 contributed in

inducing apoptosis in cells that were unresponsive toward paclitaxel (Tomko et al.

2019).

Anandamide induces a non-apoptotic form of cell death in bax/ apoptosis

resistance colorectal tumor cells (HCT116). It eliminates the resistant cells via CB

receptor-independent manner. It is observed that colorectal cancer cells have

increased expression of COX-2. Anandamide promotes cell death in apoptotic

defective cells that express COX-2 (Patsos et al. 2010). Furthermore, COX-2 is

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