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Annona muricata leaves induce G₁ cell cycle arrest and apoptosis through mitochondria-mediated pathway in human HCT-116 and HT-29 colon cancer cells

Zorofchian Moghadamtousi S, Karimian H, Rouhollahi E, Paydar M, Fadaeinasab M, Abdul Kadir H

J Ethnopharmacol, 2014 Oct 28;156:277-89.
PMID: 25195082 DOI: 10.1016/j.jep.2014.08.011

ETHNOPHARMACOLOGICAL RELEVANCE: Annona muricata known as "the cancer killer" has been widely used in the traditional medicine for the treatment of cancer and tumors. The purpose of this study is to investigate the anticancer properties of ethyl acetate extract of Annona muricata leaves (EEAM) on HT-29 and HCT-116 colon cancer cells and the underlying mechanisms.
MATERIALS AND METHODS: The effect of EEAM on the cell proliferation of HT-29 and HCT-116 cells was analyzed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) assay. High content screening system (HCS) was applied to investigate the cell membrane permeability, mitochondrial membrane potential (MMP), nuclear condensation and cytochrome c translocation from mitochondria to cytosol. Reactive oxygen species (ROS) formation, lactate dehydrogenase (LDH) release and activation of caspase-3/7, -8 and -9 were measured while treatment. Flow cytometric analysis was used to determine the cell cycle distribution and phosphatidylserine externalization. The protein expression of Bax and Bcl-2 was determined using immunofluorescence analysis. In addition, the potential of EEAM to suppress the migration and invasion of colon cancer cells was also examined.
RESULTS: EEAM exerted significant cytotoxic effects on HCT-116 and HT-29 cells as determined by MTT and LDH assays. After 24 h treatment, EEAM exhibited the IC₅₀ value of 11.43 ± 1.87 µg/ml and 8.98 ± 1.24 µg/ml against HT-29 and HCT-116 cells, respectively. Flow cytometric analysis demonstrated the cell cycle arrest at G1 phase and phosphatidylserine externalization confirming the induction of apoptosis. EEAM treatment caused excessive accumulation of ROS followed by disruption of MMP, cytochrome c leakage and activation of the initiator and executioner caspases in both colon cancer cells. Immunofluorescence analysis depicted the up-regulation of Bax and down-regulation of Bcl-2 proteins while treated with EEAM. Furthermore, EEAM conspicuously blocked the migration and invasion of HT-29 and HCT-116 cells.
CONCLUSIONS: These findings provide a scientific basis for the use of A. muricata leaves in the treatment of cancer, although further in vivo studies are still required.

Matched MeSH terms: Mitochondria/drug effects*
Fulltext Inhibition of mitochondrial cytochrome c release and suppression of caspases by gamma-tocotrienol prevent apoptosis and delay aging in stress-induced premature senescence of skin fibroblasts

Makpol S, Abdul Rahim N, Hui CK, Ngah WZ

Oxid Med Cell Longev, 2012;2012:785743.
PMID: 22919441 DOI: 10.1155/2012/785743

In this study, we determined the molecular mechanism of γ-tocotrienol (GTT) in preventing cellular aging by focusing on its anti-apoptotic effect in stress-induced premature senescence (SIPS) model of human diploid fibroblasts (HDFs). Results obtained showed that SIPS exhibited senescent-phenotypic characteristic, increased expression of senescence-associated β-galactosidase (SA β-gal) and promoted G(0)/G(1) cell cycle arrest accompanied by shortening of telomere length with decreased telomerase activity. Both SIPS and senescent HDFs shared similar apoptotic changes such as increased Annexin V-FITC positive cells, increased cytochrome c release and increased activation of caspase-9 and caspase-3 (P < 0.05). GTT treatment resulted in a significant reduction of Annexin V-FITC positive cells, inhibited cytochrome c release and decreased activation of caspase-9 and caspase-3 (P < 0.05). Gene expression analysis showed that GTT treatment down regulated BAX mRNA, up-regulated BCL2A1 mRNA and decreased the ratio of Bax/Bcl-2 protein expression (P < 0.05) in SIPS. These findings suggested that GTT inhibits apoptosis by modulating the upstream apoptosis cascade, causing the inhibition of cytochrome c release from the mitochondria with concomitant suppression of caspase-9 and caspase-3 activation. In conclusion, GTT delays cellular senescence of human diploid fibroblasts through the inhibition of intrinsic mitochondria-mediated pathway which involved the regulation of pro- and anti-apoptotic genes and proteins.

Matched MeSH terms: Mitochondria/drug effects
Fulltext Induction of selective cytotoxicity and apoptosis in human T4-lymphoblastoid cell line (CEMss) by boesenbergin a isolated from boesenbergia rotunda rhizomes involves mitochondrial pathway, activation of caspase 3 and G2/M phase cell cycle arrest

Ng KB, Bustamam A, Sukari MA, Abdelwahab SI, Mohan S, Buckle MJ, et al.

BMC Complement Altern Med, 2013;13:41.
PMID: 23432947 DOI: 10.1186/1472-6882-13-41

Boesenbergia rotunda (Roxb.) Schlecht (family zingiberaceae) is a rhizomatous herb that is distributed from north-eastern India to south-east Asia, especially in Indonesia, Thailand and Malaysia. Previous research has shown that the crude extract of this plant has cytotoxic properties. The current study examines the cytotoxic properties of boesenbergin A isolated from Boesenbergia rotunda.

Matched MeSH terms: Mitochondria/drug effects*
Lauric acid alleviates insulin resistance by improving mitochondrial biogenesis in THP-1 macrophages

Tham YY, Choo QC, Muhammad TST, Chew CH

Mol Biol Rep, 2020 Dec;47(12):9595-9607.
PMID: 33259010 DOI: 10.1007/s11033-020-06019-9

Mitochondrial dysfunction plays a crucial role in the central pathogenesis of insulin resistance and type 2 diabetes mellitus. Macrophages play important roles in the pathogenesis of insulin resistance. Lauric acid is a 12-carbon medium chain fatty acid (MCFA) found abundantly in coconut oil or palm kernel oil and it comes with multiple beneficial effects. This research objective was to uncover the effects of the lauric acid on glucose uptake, mitochondrial function and mitochondrial biogenesis in insulin-resistant macrophages. THP-1 monocytes were differentiated into macrophages and induce insulin resistance, before they were treated with increasing doses of lauric acid (5 μM, 10 μM, 20 μM, and 50 μM). Glucose uptake assay, cellular ROS and ATP production assays, mitochondrial content and membrane potential assay were carried out to analyse the effects of lauric acid on insulin resistance and mitochondrial biogenesis in the macrophages. Quantitative RT-PCR (qRT-PCR) and western blot analysis were also performed to determine the expression of the key regulators. Insulin-resistant macrophages showed lower glucose uptake, GLUT-1 and GLUT-3 expression, and increased hallmarks of mitochondrial dysfunction. Interestingly, lauric acid treatment upregulated glucose uptake, GLUT-1 and GLUT-3 expressions. The treatment also restored the mitochondrial biogenesis in the insulin-resistant macrophages by improving ATP production, oxygen consumption, mitochondrial content and potential, while it promoted the expression of mitochondrial biogenesis regulator genes such as TFAM, PGC-1α and PPAR-γ. We show here that lauric acid has the potential to improve insulin sensitivity and mitochondrial dysregulation in insulin-resistant macrophages.

Matched MeSH terms: Mitochondria/drug effects*
Fulltext The Chemopreventive Effect of Tanacetum Polycephalum Against LA7-Induced Breast Cancer in Rats and the Apoptotic Effect of a Cytotoxic Sesquiterpene Lactone in MCF7 Cells: A Bioassay-Guided Approach

Karimian H, Fadaeinasab M, Moghadamtousi SZ, Hajrezaei M, Zahedifard M, Razavi M, et al.

Cell Physiol Biochem, 2015;36(3):988-1003.
PMID: 26087920 DOI: 10.1159/000430273

BACKGROUND: Tanacetum polycephalum L. Schultz-Bip is a member of the Asteraceae family. This study evaluated the chemopreventive effect of a T. polycephalum hexane extract (TPHE) using in in vivo and in vitro models.
METHODS AND RESULTS: Five groups of rats: normal control, cancer control, TPHE low dose, TPHE high dose and positive control (tamoxifen) were used for the in vivo study. Histopathological examination showed that TPHE significantly suppressed the carcinogenic effect of LA7 tumour cells. The tumour sections from TPHE-treated rats demonstrated significantly reduced expression of Ki67 and PCNA compared to the cancer control group. Using a bioassay-guided approach, the cytotoxic compound of TPHE was identified as a tricyclic sesquiterpene lactone, namely, 8β- hydroxyl- 4β, 15- dihydrozaluzanin C (HDZC). Signs of early and late apoptosis were observed in MCF7 cells treated with HDZC and were attributed to the mitochondrial intrinsic pathway based on the up-regulation of Bax and the down-regulation of Bcl-2. HDZC induced cell cycle arrest in MCF7 cells and increased the expression of p21 and p27 at the mRNA and protein levels.
CONCLUSION: This results of this study substantiate the anticancer effect of TPHE and highlight the involvement of HDZC as one of the contributing compounds that act by initiating mitochondrial-mediated apoptosis.

Matched MeSH terms: Mitochondria/drug effects
Fulltext Artonin E Induces Apoptosis via Mitochondrial Dysregulation in SKOV-3 Ovarian Cancer Cells

Rahman MA, Ramli F, Karimian H, Dehghan F, Nordin N, Ali HM, et al.

PLoS One, 2016;11(3):e0151466.
PMID: 27019365 DOI: 10.1371/journal.pone.0151466

Artonin E is a prenylated flavonoid isolated from the stem bark of Artocarpus elasticus Reinw.(Moraceae). This study aimed to investigate the apoptotic mechanisms induced by artonin E in a metastatic human ovarian cancer cell line SKOV-3 in vitro. MTT assay, clonogenic assay, acridine orange and propidium iodide double staining, cell cycle and annexin V analyses were performed to explore the mode of artonin E-induced cell death at different time points. DNA laddering, activation of caspases-3, -8, and -9, multi-parametric cytotoxicity-3 analysis by high-content screening, measurement of reactive oxygen species generation, and Western blot were employed to study the pathways involved in the apoptosis. MTT results showed that artonin E inhibited the growth of SKOV-3 cells, with IC50 values of 6.5±0.5 μg/mL after 72 h treatment, and showed less toxicity toward a normal human ovarian cell line T1074, with IC50 value of 32.5±0.5 μg/mL. Results showed that artonin E induced apoptosis and cell cycle arrest at the S phase. This compound also promoted the activation of caspases-3, -8, and -9. Further investigation into the depletion of mitochondrial membrane potential and release of cytochrome c revealed that artonin E treatment induced apoptosis via regulation of the expression of pro-survival and pro-apoptotic Bcl-2 family members. The expression levels of survivin and HSP70 proteins were also down regulated in SKOV-3 cells treated with artonin E. We propose that artonin E induced an antiproliferative effect that led to S phase cell cycle arrest and apoptosis through dysregulation of mitochondrial pathways, particularly the pro- and anti-apoptosis signaling pathways.

Matched MeSH terms: Mitochondria/drug effects*