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1'S-1'-acetoxyeugenol acetate: a new chemotherapeutic natural compound against MCF-7 human breast cancer cells

Hasima N, Aun LI, Azmi MN, Aziz AN, Thirthagiri E, Ibrahim H, et al.

Phytomedicine, 2010 Oct;17(12):935-9.
PMID: 20729047 DOI: 10.1016/j.phymed.2010.03.011

Medicinal plants containing active natural compounds have been used as an alternative treatment for cancer patients in many parts of the world especially in Asia (Itharat et al. 2004). In this report, we describe the cytotoxic and apoptotic properties of 1'S-1'-acetoxyeugenol acetate (AEA), an analogue of 1'S-1'-acetoxychavicol acetate (ACA), isolated from the Malaysian ethno-medicinal plant Alpinia conchigera Griff (Zingiberaceae) on human breast cancer cells. Data from MTT cell viability assays indicated that AEA induced both time- and dose-dependent cytotoxicity with an IC(50) value of 14.0 μM within 36 h of treatment on MCF-7 cells, but not in HMEC normal control cells. Both annexin V-FITC/PI flow cytometric analysis and DNA fragmentation assays confirmed that AEA induced cell death via apoptosis. AEA was also found to induce cell cycle arrest in MCF-7 cells at the G(0)/G(1) phase with no adverse cell cycle arrest effects on HMEC normal control cells. It was concluded that AEA isolated from the Malaysian tropical ginger represents a potential chemotherapeutic agent against human breast cancer cells with higher cytotoxicity potency than its analogue, ACA.

Matched MeSH terms: Benzyl Alcohols/isolation & purification; Benzyl Alcohols/pharmacology; Benzyl Alcohols/therapeutic use
Fulltext Chemicals Constituents Isolated from Cultivate Alpinia conchigera Griff. and Antimicrobial Activity

Taib MNAM, Anuar N, Hanafiah KM, Al-Shammary AAK, Saaid M, Awang K

Trop Life Sci Res, 2020 Apr;31(1):159-178.
PMID: 32963717 DOI: 10.21315/tlsr2020.31.1.10

Alpinia conchigera Griff. is a plant species from the family Zingiberaceae. Coloquially known as wild ginger, Alpinia conchigera Griff. is used as food condiment and for traditional treatment of skin diseases. Isolation studies to identify bioactive compounds of rhizomes of Alpinia conchigera yielded seven compounds; 1'S-1'-acetoxychavicol acetate (1), trans-p-coumaryl diacetate (2), p-hydroxycinnamyl acetate (3), 1'S-1'-hydroxychavicol acetate (4) p-hydroxybenzaldehyde (5), stigmasterol (6) and β-sitosterol (7). Compounds 1, 2 and 5 were evaluated for antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA). Among the compounds tested, Compound 1 showed good antimicrobial activity against the strain of MRSA with minimum inhibition concentration (MIC) value of 0.5 mg/mL. Meanwhile, Compounds 2 and 5 exhibited moderate activity with MIC value between 1.0 and 2.0 mg/mL. These findings indicate antimicrobial potential of 1'S-1'-acetoxychavicol acetate (1), compound derived from rhizome of Alpinia conchigera Griff. against MRSA, which warrant further investigation.

Matched MeSH terms: Benzyl Alcohols
Fulltext Some characteristics and functional properties of Chunma (Gastrodia Elata) as a food supplement: A short review

Jaswir, I., Octavianti, F., Lestari, W., Hendri, R., Ahmad, H.

International Food Research Journal, 2017;24(101):0-0.
MyJurnal

Gastrodin elata blume (Tianma in Chinese, Chunma in Korean) is a perennial parasitic herbaceous plant native to Korea, Japan and China (Chae et al., 2008). The plant has recently received very good attention, especially in Korea, due to its excellent health-promoting properties. This plant is reported to have excellent antioxidant, anticancer and anti-inflammatory properties. This paper briefly reviews some characteristics and functional properties of Chunma.

Matched MeSH terms: Benzyl Alcohols
Fulltext Anti-Cancer Effects of Synergistic Drug-Bacterium Combinations on Induced Breast Cancer in BALB/c Mice

Subramaniam M, Arshad NM, Mun KS, Malagobadan S, Awang K, Nagoor NH

Biomolecules, 2019 10 18;9(10).
PMID: 31635311 DOI: 10.3390/biom9100626

Cancer development and progression are extremely complex due to the alteration of various genes and pathways. In most cases, multiple agents are required to control cancer progression. The purpose of this study is to investigate, using a mouse model, the synergistic interactions of anti-cancer agents, 1'-S-1'-acetoxychavicol acetate (ACA), Mycobacterium indicus pranii (MIP), and cisplatin (CDDP) in double and triple combinations to treat chemo-sensitize and immune-sensitize breast cancer. Changes in tumor volume and body weight were monitored. Organs were harvested and stained using hematoxylin-eosin for histopathological assessment. Milliplex enzyme-linked immunosorbent assay (ELISA) was performed to determine cytokine levels, while immunohistochemistry (IHC) was conducted on tumor biopsies to verify systemic drug effects. In vivo mouse models showed tumor regression with maintenance of regular body weight for all the different treatment regimens. IHC results provided conclusive evidence indicating that combination regimens were able to down-regulate nuclear factor kappa-B activation and reduce the expression of its regulated pro-inflammatory proteins. Reduction of pro-inflammatory cytokines (e.g., IL-6, TNF-α, and IFN-ɣ) levels were observed when using the triple combination, which indicated that the synergistic drug combination was able to significantly control cancer progression. In conclusion, ACA, MIP, and CDDP together serve as promising candidates for further development and for subsequent clinical trials against estrogen-sensitive breast cancer.

Matched MeSH terms: Benzyl Alcohols/chemical synthesis; Benzyl Alcohols/pharmacology*; Benzyl Alcohols/chemistry
Fulltext Anti-proliferative, apoptotic induction, and anti-migration effects of hemi-synthetic 1'S-1'-acetoxychavicol acetate analogs on MDA-MB-231 breast cancer cells

Liew SK, Azmi MN, In L, Awang K, Nagoor NH

Drug Des Devel Ther, 2017;11:2763-2776.
PMID: 29075101 DOI: 10.2147/DDDT.S130349

Nine analogs of 1'S-1'-acetoxychavicol acetate (ACA) were hemi-synthesized and evaluated for their anticancer activities against seven human cancer cell lines. The aim of this study was to investigate the anti-proliferative, apoptotic, and anti-migration effects of these compounds and to explore the plausible underlying mechanisms of action. We found that ACA and all nine analogs were non toxic to human mammary epithelial cells (HMECs) used as normal control cells, and only ACA, 1'-acetoxyeugenol acetate (AEA), and 1'-acetoxy-3,5-dimethoxychavicol acetate (AMCA) inhibited the growth of MDA-MB-231 breast cancer cells with a half-maximal inhibitory concentration (IC50) value of <30.0 μM based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay results, and were selected for further investigation. DNA fragmentation assays showed that these three compounds markedly induced apoptosis of MDA-MB-231 cells. Western blot analysis revealed increased expression levels of cleaved PARP, p53, and Bax, while decreased expression levels of Bcl-2 and Bcl-xL were seen after treatment, indicating that apoptosis was induced via the mitochondrial pathway. Moreover, ACA, AEA, and AMCA effectively inhibited the migration of MDA-MB-231 cells. They also downregulated the expression levels of pFAK/FAK and pAkt/Akt via the integrin β1-mediated signaling pathway. Collectively, ACA and its hemi-synthetic analogs, AEA and AMCA are seen as potential anticancer agents following their abilities to suppress growth, induce apoptosis, and inhibit migration of breast cancer cells.

Matched MeSH terms: Benzyl Alcohols/chemical synthesis; Benzyl Alcohols/pharmacology*; Benzyl Alcohols/chemistry
Effectiveness of amylmetacresol and 2,4-dichlorobenzyl alcohol throat lozenges in patients with acute sore throat due to upper respiratory tract infection: a systematic review protocol

Tan TW, Chen BC, Tan HL, Chang CM

JBI Database System Rev Implement Rep, 2017 Apr;15(4):862-872.
PMID: 28398972 DOI: 10.11124/JBISRIR-2016-003034

REVIEW QUESTION/OBJECTIVE: This review aims to determine the best available evidence related to the effectiveness of amylmetacresol and 2,4-dichlorobenzyl alcohol throat lozenges in patients with acute sore throat due to upper respiratory tract infection (URTI). The objective is to examine the analgesic properties of amylmetacresol and 2,4-dichlorobenzyl alcohol (AMC/DCBA) throat lozenge comparing with placebo for the relief of pain in patients with acute sore throat due to URTIs.The review question is:More specifically, the objectives are to.

Matched MeSH terms: Benzyl Alcohols/administration & dosage*
Fulltext The apoptotic effect of 1's-1'-acetoxychavicol acetate from Alpinia conchigera on human cancer cells

Awang K, Azmi MN, Aun LI, Aziz AN, Ibrahim H, Nagoor NH

Molecules, 2010 Nov;15(11):8048-59.
PMID: 21063268 DOI: 10.3390/molecules15118048

1'-(S)-1'-Acetoxychavicol acetate (ACA) isolated from the Malaysian ethno-medicinal plant Alpinia conchigera Griff. was investigated for its potential as an anticancer drug. In this communication, we describe the cytotoxic and apoptotic properties of ACA on five human tumour cell lines. Data from MTT cell viability assays indicated that ACA induced both time- and dose-dependent cytotoxicity on all tumour cell lines tested and had no adverse cytotoxic effects on normal cells. Total mortality of the entire tumour cell population was achieved within 30 hrs when treated with ACA at 40.0 µM concentration. Flow cytometric analysis for annexin-V and PI dual staining demonstrated that cell death occurred via apoptosis, followed by secondary necrosis. The apoptotic effects of ACA were confirmed via the DNA fragmentation assay, in which consistent laddering of genomic DNA was observed for all tumour cell lines after a 24 hrs post-treatment period at the IC(50) concentration of ACA. A cell cycle analysis using PI staining also demonstrated that ACA induced cell cycle arrest at the G(0)/G(1) phase, corresponding to oral tumour cell lines. In conclusion, ACA exhibits enormous potential for future development as a chemotherapeutic drug against various malignancies.

Matched MeSH terms: Benzyl Alcohols/isolation & purification; Benzyl Alcohols/pharmacology*
In vitro inhibitory mechanisms and molecular docking of 1'-S-1'-acetoxychavicol acetate on human cytochrome P450 enzymes

Haque AKMM, Leong KH, Lo YL, Awang K, Nagoor NH

Phytomedicine, 2017 Jul 15;31:1-9.
PMID: 28606510 DOI: 10.1016/j.phymed.2017.05.002

BACKGROUND: The compound, 1'-S-1'-acetoxychavicol acetate (ACA), isolated from the rhizomes of a Malaysian ethno-medicinal plant, Alpinia conchigera Griff. (Zingiberaceae), was previously shown to have potential in vivo antitumour activities. In the development of a new drug entity, potential interactions of the compound with the cytochrome P450 superfamily metabolizing enzymes need to be ascertain.
PURPOSE: The concomitant use of therapeutic drugs may cause potential drug-drug interactions by decreasing or increasing plasma levels of the administered drugs, leading to a suboptimal clinical efficacy or a higher risk of toxicity. Thus, evaluating the inhibitory potential of a new chemical entity, and to clarify the mechanism of inhibition and kinetics in the various CYP enzymes is an important step to predict drug-drug interactions.
STUDY DESIGN: This study was designed to assess the potential inhibitory effects of Alpinia conchigera Griff. rhizomes extract and its active constituent, ACA, on nine c-DNA expressed human cytochrome P450s (CYPs) enzymes using fluorescent CYP inhibition assay.
METHODS/RESULTS: The half maximal inhibitory concentration (IC50) of Alpinia conchigera Griff. rhizomes extract and ACA was determined for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. A. conchigera extract only moderately inhibits on CYP3A4 (IC50 = 6.76 ± 1.88µg/ml) whereas ACA moderately inhibits the activities of CYP1A2 (IC50 = 4.50 ± 0.10µM), CYP2D6 (IC50 = 7.50 ± 0.17µM) and CYP3A4 (IC50 = 9.50 ± 0.57µM) while other isoenzymes are weakly inhibited. In addition, mechanism-based inhibition studies reveal that CYP1A2 and CYP3A4 exhibited non-mechanism based inhibition whereas CYP2D6 showed mechanism-based inhibition. Lineweaver-Burk plots depict that ACA competitively inhibited both CYP1A2 and CYP3A4, with a Ki values of 2.36 ± 0.03 µM and 5.55 ± 0.06µM, respectively, and mixed inhibition towards CYP2D6 with a Ki value of 4.50 ± 0.08µM. Further, molecular docking studies show that ACA is bound to a few key amino acid residues in the active sites of CYP1A2 and CYP3A4, while one amino residue of CYP2D6 through predominantly Pi-Pi interactions.
CONCLUSION: Overall, ACA may demonstrate drug-drug interactions when co-administered with other therapeutic drugs that are metabolized by CYP1A2, CYP2D6 or CYP3A4 enzymes. Further in vivo studies, however, are needed to evaluate the clinical significance of these interactions.

Matched MeSH terms: Benzyl Alcohols/pharmacology*; Benzyl Alcohols/chemistry
Acute and 28-day sub-acute intravenous toxicity studies of 1'-S-1'-acetoxychavicol acetate in rats

Abdalla YOA, Nyamathulla S, Shamsuddin N, Arshad NM, Mun KS, Awang K, et al.

Toxicol Appl Pharmacol, 2018 10 01;356:204-213.
PMID: 30138658 DOI: 10.1016/j.taap.2018.08.014

1'-S-1'-acetoxychavicol acetate (ACA) has been previously reported to reduce tumor volume in nude mice, at an effective dose of 1.56 mg/kg body weight. However, the detailed toxicological profile for ACA has not yet been performed. Herein, we investigated the toxicity of intravenous administration of ACA in male and female Sprague-Dawley rats, both acutely (with single doses of 2.00, 4.00 and 6.66 mg/kg body weight, for 14 days), and sub-acutely (with weekly injections of 0.66, 1.33, and 2.22 mg/kg, for 28 days). In both toxicity studies, treatment with ACA did not affect behavior, food/water intake or body weight, nor did it induce any changes in clinically relevant hematological and biochemical parameters or mortality, suggesting that the LD50 of ACA was higher than 6.66 mg/kg body weight, regardless of sex. Sub-acutely, there was however, mild focal inflammation of kidneys and lobular hepatitis, but these were not associated with significant functional adverse effects. Therefore, the no-observed-adverse-effect level (NOAEL) for intravenous administration of ACA in the present 28-day sub-acute study was 2.22 mg/kg body weight, in both male and female rats. These findings provide useful information regarding the safety of ACA use in a healthy, non-tumor-bearing rat model.

Matched MeSH terms: Benzyl Alcohols/administration & dosage; Benzyl Alcohols/toxicity*
Fulltext 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

Sok SP, Arshad NM, Azmi MN, Awang K, Ozpolat B, Hasima Nagoor N

PLoS One, 2017;12(2):e0171329.
PMID: 28158287 DOI: 10.1371/journal.pone.0171329

Autophagy plays a role in deciding the fate of cells by inducing either survival or death. 1'S-1-acetoxychavicol acetate (ACA) is a phenylpropanoid isolated from rhizomes of Alpinia conchigera and has been reported previously on its apoptotic effects on various cancers. However, the effect of ACA on autophagy remains ambiguous. The aims of this study were to investigate the autophagy-inducing ability of ACA in human non-small cell lung cancer (NSCLC), and to determine its role as pro-survival or pro-death mechanism. Cell viability assay was conducted using MTT. The effect of autophagy was assessed by acridine orange staining, GFP-LC3 punctate formation assay, and protein level were analysed using western blot. Annexin V-FITC/PI staining was performed to detect percentage of cells undergoing apoptosis by using flow cytometry. ACA inhibits the cell viability and induced formation of cytoplasmic vacuoles in NSCLC cells. Acidic vesicular organelles and GFP-LC3 punctate formation were increased in response to ACA exposure in A549 and SK-LU-1 cell lines; implying occurrence of autophagy. In western blot, accumulation of LC3-II accompanied by degradation of p62 was observed, which further confirmed the full flux of autophagy induction by ACA. The reduction of Beclin-1 upon ACA treatment indicated the Beclin-1-independent autophagy pathway. An early autophagy inhibitor, 3-methyaldenine (3-MA), failed to suppress the autophagy triggered by ACA; validating the existence of Beclin-1-independent autophagy. Silencing of LC3-II using short interfering RNA (siRNA) abolished the autophagy effects, enhancing the cytotoxicity of ACA through apoptosis. This proposed ACA triggered a pro-survival autophagy in NSCLC cells. Consistently, co-treatment with lysosomal inhibitor, chloroquine (CQ), exerted a synergistic effect resulting in apoptosis. Our findings suggested ACA induced pro-survival autophagy through Beclin-1-independent pathway in NSCLC. Hence, targeting autophagy pathway using autophagy inhibitor such as CQ represented a novel promising approach to potentiate the cytotoxicity of ACA through apoptosis in NSCLC.

Matched MeSH terms: Benzyl Alcohols/pharmacology*
Fulltext 1'-Acetoxychavicol acetate inhibits growth of human oral carcinoma xenograft in mice and potentiates cisplatin effect via proinflammatory microenvironment alterations

In LL, Arshad NM, Ibrahim H, Azmi MN, Awang K, Nagoor NH

BMC Complement Altern Med, 2012;12:179.
PMID: 23043547 DOI: 10.1186/1472-6882-12-179

Oral cancers although preventable, possess a low five-year survival rate which has remained unchanged over the past three decades. In an attempt to find a more safe, affordable and effective treatment option, we describe here the use of 1'S-1'-acetoxychavicol acetate (ACA), a component of Malaysian ginger traditionally used for various medicinal purposes.

Matched MeSH terms: Benzyl Alcohols/pharmacology; Benzyl Alcohols/therapeutic use*
Fulltext Inactivation of nuclear factor κB by MIP-based drug combinations augments cell death of breast cancer cells

Subramaniam M, Liew SK, In L, Awang K, Ahmed N, Nagoor NH

Drug Des Devel Ther, 2018;12:1053-1063.
PMID: 29750018 DOI: 10.2147/DDDT.S141925

Background: Drug combination therapy to treat cancer is a strategic approach to increase successful treatment rate. Optimizing combination regimens is vital to increase therapeutic efficacy with minimal side effects.
Materials and methods: In the present study, we evaluated the in vitro cytotoxicity of double and triple combinations consisting of 1'S-1'-acetoxychavicol acetate (ACA), Mycobacterium indicus pranii (MIP) and cisplatin (CDDP) against 14 various human cancer cell lines to address the need for more effective therapy. Our data show synergistic effects in MCF-7 cells treated with MIP:ACA, MIP:CDDP and MIP:ACA:CDDP combinations. The type of interaction between MIP, ACA and CDDP was evaluated based on combination index being <0.8 for synergistic effect. Identifying the mechanism of cell death based on previous studies involved intrinsic apoptosis and nuclear factor kappa B (NF-κB) and tested in Western blot analysis. Inactivation of NF-κB was confirmed by p65 and IκBα, while intrinsic apoptosis pathway activation was confirmed by caspase-9 and Apaf-1 expression.
Results: All combinations confirmed intrinsic apoptosis activation and NF-κB inactivation.
Conclusion: Double and triple combination regimens that target induction of the same death mechanism with reduced dosage of each drug could potentially be clinically beneficial in reducing dose-related toxicities.

Matched MeSH terms: Benzyl Alcohols/pharmacology*; Benzyl Alcohols/chemistry
Fulltext Alterations of microRNA expression patterns in human cervical carcinoma cells (Ca Ski) toward 1'S-1'-acetoxychavicol acetate and cisplatin

Phuah NH, In LL, Azmi MN, Ibrahim H, Awang K, Nagoor NH

Reprod Sci, 2013 May;20(5):567-78.
PMID: 23012319 DOI: 10.1177/1933719112459220

The aims of this study were to investigate the combined effects of a natural compound 1'S-1'-acetoxychavicol acetate (ACA) with cisplatin (CDDP) on HPV-positive human cervical carcinoma cell lines (Ca Ski-low cisplatin sensitivity and HeLa-high cisplatin sensitivity), and to identify microRNAs (miRNAs) modulated in response toward ACA and/or CDDP. It was revealed that both ACA and CDDP induced dose- and time-dependent cytotoxicity when used as a stand-alone agent, while synergistic effects were observed when used in combination with a combination index (CI) value of 0.74 ± 0.01 and 0.85 ± 0.01 in Ca Ski and HeLa cells, respectively. A total of 25 miRNAs were found to be significantly differentially expressed in response to ACA and/or CDDP. These include hsa-miR-138, hsa-miR-210, and hsa-miR-744 with predicted gene targets involved in signaling pathways regulating apoptosis and cell cycle progression. In conclusion, ACA acts as a chemosensitizer which synergistically potentiates the cytotoxic effect of CDDP in cervical cancer cells. The altered miRNA expression upon administration of ACA and/or CDDP suggests that miRNAs play an important role in anticancer drug responses, which can be manipulated for therapeutic purposes.

Matched MeSH terms: Benzyl Alcohols/pharmacology
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

Arshad NM, In LL, Soh TL, Azmi MN, Ibrahim H, Awang K, et al.

Oncotarget, 2015 Jun 30;6(18):16151-67.
PMID: 26158863

Previous 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.

Matched MeSH terms: Benzyl Alcohols/pharmacology*
Fulltext Down-Regulation of MicroRNA-210 Confers Sensitivity towards 1'S-1'-Acetoxychavicol Acetate (ACA) in Cervical Cancer Cells by Targeting SMAD4

Phuah NH, Azmi MN, Awang K, Nagoor NH

Mol Cells, 2017 Apr;40(4):291-298.
PMID: 28401751 DOI: 10.14348/molcells.2017.2285

MicroRNAs (miRNAs) are short non-coding RNAs that regulate genes posttranscriptionally. Past studies have reported that miR-210 is up-regulated in many cancers including cervical cancer, and plays a pleiotropic role in carcinogenesis. However, its role in regulating response towards anti-cancer agents has not been fully elucidated. We have previously reported that the natural compound 1'S-1'-acetoxychavicol acetate (ACA) is able to induce cytotoxicity in various cancer cells including cervical cancer cells. Hence, this study aims to investigate the mechanistic role of miR-210 in regulating response towards ACA in cervical cancer cells. In the present study, we found that ACA down-regulated miR-210 expression in cervical cancer cells, and suppression of miR-210 expression enhanced sensitivity towards ACA by inhibiting cell proliferation and promoting apoptosis. Western blot analysis showed increased expression of mothers against decapentaplegic homolog 4 (SMAD4), which was predicted as a target of miR-210 by target prediction programs, following treatment with ACA. Luciferase reporter assay confirmed that miR-210 binds to sequences in 3'UTR of SMAD4. Furthermore, decreased in SMAD4 protein expression was observed when miR-210 was overexpressed. Conversely, SMAD4 protein expression increased when miR-210 expression was suppressed. Lastly, we demonstrated that overexpression of SMAD4 augmented the anti-proliferative and apoptosis-inducing effects of ACA. Taken together, our results demonstrated that down-regulation of miR-210 conferred sensitivity towards ACA in cervical cancer cells by targeting SMAD4. These findings suggest that combination of miRNAs and natural compounds could provide new strategies in treating cervical cancer.

Matched MeSH terms: Benzyl Alcohols/pharmacology*
Fulltext Development and Evaluation of 1'-Acetoxychavicol Acetate (ACA)-Loaded Nanostructured Lipid Carriers for Prostate Cancer Therapy

Subramaniam B, Arshad NM, Malagobadan S, Misran M, Nyamathulla S, Mun KS, et al.

Pharmaceutics, 2021 Mar 24;13(4).
PMID: 33804975 DOI: 10.3390/pharmaceutics13040439

1'-acetoxychavicol acetate (ACA) extracted from the rhizomes of Alpinia conchigera Griff (Zingiberaceae) has been shown to deregulate the NF-ĸB signaling pathway and induce apoptosis-mediated cell death in many cancer types. However, ACA is a hydrophobic ester, with poor solubility in an aqueous medium, limited bioavailability, and nonspecific targeting in vivo. To address these problems, ACA was encapsulated in a nanostructured lipid carrier (NLC) anchored with plerixafor octahydrochloride (AMD3100) to promote targeted delivery towards C-X-C chemokine receptor type 4 (CXCR4)-expressing prostate cancer cells. The NLC was prepared using the melt and high sheer homogenization method, and it exhibited ideal physico-chemical properties, successful encapsulation and modification, and sustained rate of drug release. Furthermore, it demonstrated time-based and improved cellular uptake, and improved cytotoxic and anti-metastatic properties on PC-3 cells in vitro. Additionally, the in vivo animal tumor model revealed significant anti-tumor efficacy and reduction in pro-tumorigenic markers in comparison to the placebo, without affecting the weight and physiological states of the nude mice. Overall, ACA-loaded NLC with AMD3100 surface modification was successfully prepared with evidence of substantial anti-cancer efficacy. These results suggest the potential use of AMD3100-modified NLCs as a targeting carrier for cytotoxic drugs towards CXCR4-expressing cancer cells.

Matched MeSH terms: Benzyl Alcohols
1'-Acetoxychavicol acetate inhibits NLRP3-dependent inflammasome activation via mitochondrial ROS suppression

Sok SPM, Ori D, Wada A, Okude H, Kawasaki T, Momota M, et al.

Int Immunol, 2021 06 18;33(7):373-386.
PMID: 33830232 DOI: 10.1093/intimm/dxab016

The nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing (NLRP) 3 inflammasome is a multiprotein complex that triggers Caspase-1-mediated IL-1β production and pyroptosis, and its dysregulation is associated with the pathogenesis of inflammatory diseases. 1'-Acetoxychavicol acetate (ACA) is a natural compound in the rhizome of tropical ginger Alpinia species with anti-microbial, anti-allergic and anti-cancer properties. In this study, we found that ACA suppressed NLRP3 inflammasome activation in mouse bone marrow-derived macrophages and human THP-1 monocytes. ACA inhibited Caspase-1 activation and IL-1β production by NLRP3 agonists such as nigericin, monosodium urate (MSU) crystals, and ATP. Moreover, it suppressed oligomerization of the adapter molecule, apoptosis-associated speck-like protein containing a CARD (ASC), and Caspase-1-mediated cleavage of pyroptosis executor Gasdermin D. Mechanistically, ACA inhibited generation of mitochondrial reactive oxygen species (ROS) and prevented release of oxidized mitochondrial DNA, which trigger NLRP3 inflammasome activation. ACA also prevented NLRP3 inflammasome activation in vivo, as evidenced in the MSU crystal-induced peritonitis and dextran sodium sulfate-induced colitis mouse models accompanied by decreased Caspase-1 activation. Thus, ACA is a potent inhibitor of the NLRP3 inflammasome for prevention of NLRP3-associated inflammatory diseases.

Matched MeSH terms: Benzyl Alcohols/pharmacology*

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