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chemotherapy. The HCC progression was similar between plant Cannabis sativa that can activate two G-protein-coupled
[57]
the two groups, but the TCM approach showed less adverse receptors. The active ingredients of Cannabis, as well as
reactions. Moreover, survival rate at three months was their synthetic analogues, are bioactive lipids that seem to
comparable, while the test group had a better half- and block cell proliferation, reduce cell migration and inhibit
[58]
1-year survival. angiogenesis. The molecular mechanisms involved in the
antineoplastic and anti-HCC action are debated. G protein-
Man et al. studied 94 patients with unresectable HCC. coupled receptor type 1 and 2 are typically considered the
[51]
Authors compared three subgroups: (1) patients receiving cannabinoids receptors. However, these substances may
TCM with non-curative antitumor treatments of Western impact on other targets such as nuclear receptors peroxisome
Medicine; (2) patients receiving TCM alone; and (3) patients proliferator-activated receptor (PPAR)s. PPARs are ligand-
[59]
treated with non-curative antitumor treatments of Western activated transcription factors, which belong to the nuclear
Medicine or supportive treatment alone. They showed that receptor superfamily and mediate lipid metabolism, energy
patients treated with the combination schedule respect to balance and anti-inflammatory cascade. Several PPAR
[60]
patients in Western therapy alone, showed a significantly ligands have been shown to decrease HCC cell proliferation
better 1- and 2-year survival (76.0% and 55.5% vs. 55.8% and and migration through PPAR activation. Moreover, utilizing
[61]
30.8%, respectively). a PPARg knockout mice model, it was suggested that PPAR
decreases HCC carcinogenesis acting as tumor-suppressor
In 2005, Shu et al. analysed 26 RCTs reporting that gene in the liver. Notably, the synthetic cannabinoid
[52]
[62]
TCM might determine an advantage in terms of both WIN 55,212-2 seemed to increase PPAR expression leading
neoplasm response and long-term patient survival. to apoptosis in the HCC HepG2 cell line. Vara et al.
[57]
[63]
Notably, authors did not specify the kind of used natural demonstrated that D9-tetrahydrocannabinol and JWH-015
[53]
product. McCulloch et al. compared 34 RCTs, including (two kind of cannabinoids), might induce autophagy in HCC
2,815 subjects, demonstrating that Astragalus-based TCM cells stimulating the AMP-activated protein kinase pathway.
increased the efficacy of platinum chemotherapy. In 2009, Jiang et al. studying the PPAR-deficient mice, demonstrated
[64]
two meta-analyses reported data concerning the possible the accumulation of autophagic vacuoles and up-regulation
[54]
role of TCM in association with TACE. Cho and Chen of autophagic marker LC3 protein expression. These results
analyzed 30 studies showing an improved long-term are in agreement with the above reported observations by
survival in patients treated with the association between Vara et al. These authors suggested a connection between
[57]
TACE and TCM respect to the subjects who did not receive PPAR and autophagy-essential proteins in mammalian HCC.
[65]
TCM. According to this study, TCM determined a relevant Also Vara et al. reported the involvement of PPAR activation
increase in white blood cell count, a substantially lower in the anti-cancer effect of cannabinoids. The authors showed
nausea and vomiting, and a significant rise in the body that THC and JWH-015 might increase mRNA and protein
weight. Wu et al. systematically reviewed and meta- levels of PPAR inducing PPAR activation in vitro. Moreover, the
[55]
analyzed a series of Chinese RCTs concerning the efficacy authors showed that, when endoplasmic reticulum stress-
of TCM for the treatment of HCC. Authors reported related protein tribbles homolog 3 (TRIB 3) is genetically
some criticisms of the analyzed trials suggesting that inhibited, the expression of both PPAR mRNA and protein
the methodological issues were poor. Nevertheless, decreased. Indeed, TRIB 3 seemed to have a significant role
the studies with bufotoxin, astragalus (with or without in regulating cannabinoid-induced PPAR overexpression.
mylabris) and ginseng associated to TACE, showed lower Cannabinoid treatment could improve phosphorylated-
HCC recurrence and better patient survival in comparison eIF2a (an endoplasmic reticulum stress marker) and the
to TACE alone. However, authors suggested that these endoplasmic reticulum stress-related pseudokinase TRIB 3.
data should be confirmed in further well-conducted Notably, this latter is necessary for cannabinoid-induced cell
Western RCTs. death and the consequent anti-tumor effect. Regarding
[66]
the role of TRIB 3, Takahashi et al. demonstrated that it
[67]
Kanglaite (KLT) is a TCM coming from the seeds of a can downregulate PPAR transcriptional activities by protein-
tropical Asian grass called Coix. It exhibits antitumor and protein interaction in 3T3-L1 adipocytes.
immunomodulatory activity. Fu et al. performed a meta-
[56]
analysis including nine clinical trials to evaluate the efficacy of CONCLUSIONS AND FUTURE PERSPECTIVES
KLT injection combined with hepatic arterial intervention for
the treatment of unresectable HCC. KLT injection combined HCC represents one of the most common cancers worldwide
with hepatic arterial intervention respect to arterial therapy and is the third cause of neoplasm-related death. Since
alone, seemed to improve both short-term clinical efficacy chronic viral hepatitis are the main risk factors for HCC, the
and pain’s control. vaccination against hepatitis B and the treatment of both
hepatitis B and C, represent the main preventive therapies.
CANNABINOIDS Today, the potentially curative (LT, resection, ablation) and
palliative (arterial chemoembolization, sorafenib) standards
Cannabinoids are lipid mediators isolated from the hemp of care still do not protect from a relevant rate of mortality.

74 Hepatoma Research | Volume 2 | March 9, 2016