Inclusion Complex of Zerumbone with Hydroxypropyl-β-Cyclodextrin Induces Apoptosis in Liver Hepatocellular HepG2 Cells via Caspase 8/BID Cleavage Switch and Modulating Bcl2/Bax Ratio

Abstract

Zerumbone (ZER) isolated from Zingiber zerumbet was previously encapsulated with hydroxypropyl-β-cyclodextrin (HPβCD) to enhance ZER's solubility in water, thus making it highly tolerable in the human body. The anticancer effects of this new ZER-HPβCD inclusion complex via apoptosis cell death were assessed in this study for the first time in liver hepatocellular cells, HepG2. Apoptosis was ascertained by morphological study, nuclear stain, and sub-G1 cell population accumulation with G2/M arrest. Further investigations showed the release of cytochrome c and loss of mitochondrial membrane potential, proving mitochondrial dysfunction upon the ZER-HPβCD treatment as well as modulating proapoptotic and anti-apototic Bcl-2 family members. A significant increase in caspase 3/7, caspase 9, and caspase 8 was detected with the depletion of BID cleaved by caspase 8. Collectively, these results prove that a highly soluble inclusion complex of ZER-HPβCD could be a promising anticancer agent for the treatment of hepatocellular carcinoma in humans.

Mechanism of Hepatoprotective Effect ofBoesenbergia rotundain Thioacetamide-Induced Liver Damage in Rats

“…This was confirmed by the ratio Bax/Bcl-2 (Figure 3(b)) which was high in the treated groups compared to cirrhosis group and the immunohistochemistry staining of Bax and Bcl-2 (Figure 5). The ethanolic extract of BR rhizomes might contain active compounds such as the chalcone Boesenbergin A [47] and the sesquiterpene zerumbone [48] which were reported recently to induce apoptosis of liver cancer cells HepG2 through the release of cytochrome C and the formation of caspase-3 modifying the necrotic effect due to TAA intoxication to apoptosis. This modification in vivo would scale down the release of inflammatory mediators that would prevent progressive liver damage.…”

Biomedical Properties of a Natural Dietary Plant Metabolite, Zerumbone, in Cancer Therapy and Chemoprevention Trials

“…Recently, in our laboratory, ZER was made soluble by incorporating in the cyclodextrin complex. The production of the ZER-cyclodextrin complex enabled ZER to be formulated as an encapsulated natural compound ready for use, either as an injectable solution or delivered orally as an anticancer product [ 148 , 149 ]. The usefulness of encapsulated ZER complex as potential anticancer is worth future exploration through preclinical and human clinical trials to determine efficacy and safety of the product for human use.…”

Potential of Zerumbone as an Anti-Cancer Agent

“…Zerumbone can activate the Nrf2/ARE-dependent detoxification pathway induced by nuclear localization of Nrf2, which can bind to the antioxidant response element of the phase II enzyme genes, thereby suggesting an antioxidant role of zerumbone in neutralizing lipid peroxidation in liver cells to put a stop to cancer [ 48 ]. A soluble complex of zerumbone with hydroxypropyl-β-cyclodextrin (HP-β-CD) induced apoptosis and G2/M arrest along with the release of cytochrome c and loss of mitochondrial membrane potential, with a significant increase in caspase 3/7, caspase 9, and caspase 8, and with the depletion of BID that is cleaved by caspase 8 [ 118 ].…”