Recombinant human alpha fetoprotein synergistically potentiates the anti-cancer effects of 1′-S-1′-acetoxychavicol acetate when used as a complex against human tumours harbouring AFP-receptors

Abstract

PurposePrevious in vitro and in vivo studies have reported that 1′-S-1′-acetoxychavicol acetate (ACA) isolated from rhizomes of the Malaysian ethno-medicinal plant Alpinia conchigera Griff (Zingiberaceae) induces apoptosis-mediated cell death in tumour cells via dysregulation of the NF-κB pathway. However there were some clinical development drawbacks such as poor in vivo solubility, depreciation of biological activity upon exposure to an aqueous environment and non-specific targeting of tumour cells. In the present study, all the problems above were addressed using the novel drug complex formulation involving recombinant human alpha fetoprotein (rhAFP) and ACA.Experimental DesignTo study the synergistic effect of both agents on human cancer xenografts, athymic nude (Nu/Nu) mice were used and treated with various combination regimes intraperitoneally. Serum levels of tumour markers for carcinoembryonic antigen (CEA) and prostate specific antigen (PSA) were assessed using sandwich ELISA. IHC and Western blotting were also conducted on in vivo tumour biopsies to investigate the involvement of NF-κB regulated genes and inflammatory biomarkers. Quantification and correlation between drug efficacies and AFP-receptors were done using IF-IC and Pearson's correlation analysis.ResultsMice exposed to combined treatments displayed higher reductions in tumour volume compared to stand alone agents, consistent with in vitro cytotoxicity assays. Milder signs of systemic toxicity, such as loss in body weight and inflammation of vital organs were also demonstrated compared to stand alone treatments. Tumour marker levels were consistent within all rhAFP/ACA treatment groups where levels of CEA and PSA were initially elevated upon commencement of treatment, and consecutively reduced corresponding to a decrease in tumour bulk volume. Both IHC and Western blotting results indicated that the combined action of rhAFP/ACA was not only able to down-regulate NF-κB activation, but also reduce the expression of NF-κB regulated genes and inflammatory biomarkers. The efficacy of rhAFP/ACA complex was also found to be weakly negatively correlated to the level of surface AFP-receptors between tumour types.ConclusionsThis drug complex formulation shows great therapeutic potential against AFP-receptor positive tumours, and serves as a basis to overcome insoluble and non-specific anti-neoplastic molecules.

Anti-proliferative, apoptotic induction, and anti-migration effects of hemi-synthetic 1&prime;<em>S</em>-1&prime;-acetoxychavicol acetate analogs on MDA-MB-231 breast cancer cells

“…For example, ACA reduced tumor volume and side effects in vivo when used in combination with alpha-fetoprotein (AFP). 52 …”

The apoptotic effect of 1’S-1’-Acetoxychavicol Acetate (ACA) enhanced by inhibition of non-canonical autophagy in human non-small cell lung cancer cells

“…1’S-1-acetoxychavicol acetate (ACA) is a phenylpropanoid isolated from rhizomes of Alpinia conchigera Griff. Our group had previously reported the anti-cancer effects of ACA in breast (MCF-7), oral (HSC-2 and HSC-4), liver (HepG2), cervical (CaSki), lung cancer (A549) and prostate carcinoma (PC-3) via inducing apoptosis with minimal cytotoxic effect on normal human mammary cells (HMEC) and no physiological alteration in in vivo model [ 12 – 14 ]. It was reported that ACA targets NF-κB signalling pathway to alter the pro-inflammatory microenvironment environment both in vitro and in vivo [ 12 , 14 ].…”

“…Our group had previously reported the anti-cancer effects of ACA in breast (MCF-7), oral (HSC-2 and HSC-4), liver (HepG2), cervical (CaSki), lung cancer (A549) and prostate carcinoma (PC-3) via inducing apoptosis with minimal cytotoxic effect on normal human mammary cells (HMEC) and no physiological alteration in in vivo model [ 12 – 14 ]. It was reported that ACA targets NF-κB signalling pathway to alter the pro-inflammatory microenvironment environment both in vitro and in vivo [ 12 , 14 ]. Despite numerous reports on its direct interaction on signalling pathway, ACA can modulate epigenetic machinery in cancer by altering miRNA expression that eventually has an impact in the gene expression [ 15 ].…”

“…Despite numerous reports on its direct interaction on signalling pathway, ACA can modulate epigenetic machinery in cancer by altering miRNA expression that eventually has an impact in the gene expression [ 15 ]. Moreover, a synergistic anti-cancer effect was further observed in combination treatment of ACA with cisplastin or recombinant human alpha fetoprotein [ 12 , 14 , 15 ]. These studies revealed ACA as a potential anti-cancer remedy.…”

Magic Bullet and Immunotherapy against Metastasis

“…Receptor-positive embryo and cancer cells have definite benefits of targeted nutrient delivery ( Figure 1). That is why AFP loaded with the different toxins was used for the targeted chemotherapy [6,7]. The AFP receptor detection on the major immune suppressive cells -MDSC -was very promising [8,9].…”