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Molecular mechanisms of apoptosis and cell selectivity of zinc dithiocarbamates functionalized with hydroxyethyl substituents

Tan YS, Ooi KK, Ang KP, Akim AM, Cheah YK, Halim SN, et al.

J Inorg Biochem, 2015 Sep;150:48-62.
PMID: 26086852 DOI: 10.1016/j.jinorgbio.2015.06.009

In the solid state each of three binuclear zinc dithiocarbamates bearing hydroxyethyl groups, {Zn[S2CN(R)CH2CH2OH]2}2 for R = iPr (1), CH2CH2OH (2), and Me (3), and an all alkyl species, [Zn(S2CNEt2)2]2 (4), features a centrosymmetric {ZnSCS}2 core with a step topology; both 1 and 3 were isolated as monohydrates. All compounds were broadly cytotoxic, specifically against human cancer cell lines compared with normal cells, with greater potency than cisplatin. Notably, some selectivity were indicated with 2 being the most potent against human ovarian carcinoma cells (cisA2780), and 4 being more cytotoxic toward multidrug resistant human breast carcinoma cells (MCF-7R), human colon adenocarcinoma cells (HT-29), and human lung adenocarcinoma epithelial cells (A549). Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis in HT-29 cells is demonstrated via both extrinsic and intrinsic pathways. Compounds 2-4 activate the p53 gene while 1 activates both p53 and p73. Cell cycle arrest at the S and G2/M phases correlates with inhibition of HT-29 cell growth. Cell invasion is also inhibited by 1-4 which is correlated with down-regulation of NF-κB.

Matched MeSH terms: Ovarian Neoplasms
Fulltext C-kit proto-oncogene expression in uterine leiomyosarcomas: case series

Naik, V.R., Hasnan, J.

International Medical Journal Malaysia, 2008;7(2):51-54.
MyJurnal

Introduction: The proto-oncogene c-kit is the cellular homologue of the oncogene v-kit of HZ4 feline sarcoma virus. It is located on chromosome 4 (4q11-12) in the human genome. Interaction between the c-kit receptor and its ligand, stem cell factor, is essential in the development of tissues. C-kit expression has been identified in a number of different neoplasms like seminoma/dysgerminoma, and gastrointestinal stromal tumors (GIST). Recently it has been reported that c-kit is also present in leiomyosarcomas. Tyrosine kinase inhibitors (TKIs) are a promising new therapy in the treatment of cancer. These agents target cellular proteins like kit and its related homologues decreasing cellular proliferation and survival. TKIs may be helpful in treating leiomyosarcomas expressing c-kit. Materials and Methods: In this study a total of 6 cases diagnosed as leiomyosarcomas at Department of Pathology, Universiti Sains Malaysia, Kubang Kerian, Malaysia, were investigated for reactivity for c-kit using immunohistochemical stain. Stain was considered positive if more than 10 percent of the cells showed membrane or cytoplasmic positivity. Results: Two leiomyosarcomas stained faintly with c-kit and in less than 10 percent of the cells. The other 4 cases showed no staining. The control showed good membrane and cytoplasmic positivity. Conclusion: Uterine leiomyosarcomas did not express c-kit. The reason for this could be that the tumors are inherently c-kit negative. More study using larger number of cases is required to validate these findings and further molecular characterization of these mesenchymal tumors is needed to identify the true nature of these sarcomas.

Matched MeSH terms: Ovarian Neoplasms
Fulltext Chemical composition and anti-proliferative properties of flowers of Clitoria Ternatea

Neda, G.D., Rabeta, M.S., Ong, M.T.

International Food Research Journal, 2013;20(3):1229-1234.
MyJurnal

Aqueous and methanol extracts of the flowers of Clitoria ternatea (CT), a popularly
plant consumed for blue colour in Nasi Kerabu was selected to explore its cytotoxic
effect on six types of normal and cancer-origin cell lines. These included the hormone-dependent breast cancer cell line (MCF-7), non-hormone-dependent breast cancer cell
line (MDA-MB-231), human ovary cancer cell line (Caov-3), human cervical cancer cell line (Hela), human liver cancer cell line (HepG2) and human foreskin fibroblast cell line (Hs27). The anti-proliferation activities of the extracts were examined by employing colorimetric MTT (3-(4,5-dimethylthiazol-2-yl) 2,5 diphenyltetrazolium bromide) assay through time periods of 24, 48 and 72 hours. Preliminary results showed that the water extracted of CT had significant effects (p < 0.05) against MCF-7 with an IC50 value of 175.35 µg/ml. Furthermore, the aqueous and methanolic extracts were investigated by Gas Chromatogram-Mass spectrometry (GC-MS). The GC-MS chromatogram analysis of the water extracted had shown five peaks that represented components in the water extract namely mome inositol (38.7%) and pentanal (14.3%). Fifteen chemical constituents were identified in the methanol extract and the major chemical constituents were mome inositol (33.6%), cyclohexen, 1-methyl-4-(1-methylethylideme)- (7.1%), acetic acid, cyano- (6.5%) and hirsutene (5.7%). Heavy metals tested were at very low levels. The analysis conducted on the flowers provides a strong basis for emphasizing the medicinal and nutritional value of CT.

Matched MeSH terms: Ovarian Neoplasms
Fulltext 10H-3,6-Diazaphenothiazine induces G2/M phase cell cycle arrest and caspase-dependent apoptosis and inhibits cell invasion of A2780 ovarian carcinoma cells through the regulation of NF-κB and (BIRC6-XIAP) complexes

Zhang J, Ming C, Zhang W, Okechukwu PN, Morak-Młodawska B, Pluta K, et al.

Drug Des Devel Ther, 2017;11:3045-3063.
PMID: 29123378 DOI: 10.2147/DDDT.S144415

The asymptomatic properties and high treatment resistance of ovarian cancer result in poor treatment outcomes and high mortality rates. Although the fundamental chemotherapy provides promising anticancer activities, it is associated with severe side effects. The derivative of phenothiazine, namely, 10H-3,6-diazaphenothiazine (PTZ), was synthesized and reported with ideal anticancer effects in a previous paper. In this study, detailed anticancer properties of PTZ was examined on A2780 ovarian cancer cells by investigating the cytotoxicity profiles, mechanism of apoptosis, and cell invasion. Research outcomes revealed PTZ-induced dose-dependent inhibition on A2780 cancer cells (IC50 =0.62 µM), with significant less cytotoxicity toward HEK293 normal kidney cells and H9C2 normal heart cells. Generation of reactive oxygen species (ROS) and polarization of mitochondrial membrane potential (ΔΨm) suggests PTZ-induced cell death through oxidative damage. The RT2 Profiler PCR Array on apoptosis pathway demonstrated PTZ-induced apoptosis via intrinsic (mitochondria-dependent) and extrinsic (cell death receptor-dependent) pathway. Inhibition of NF-κB and subsequent inhibition of (BIRC6-XIAP) complex activities reduced the invasion rate of A2780 cancer cells penetrating through the Matrigel™ Invasion Chamber. Lastly, the cell cycle analysis hypothesizes that the compound is cytostatic and significantly arrests cell proliferation at G2/M phase. Hence, the exploration of the underlying anticancer mechanism of PTZ suggested its usage as promising chemotherapeutic agent.

Matched MeSH terms: Ovarian Neoplasms/drug therapy*
Anti-proliferative and pro-apoptotic effects from sequenced combinations of andrographolide and cisplatin on ovarian cancer cell lines

Yunos NM, Mutalip SS, Jauri MH, Yu JQ, Huq F

Anticancer Res, 2013 Oct;33(10):4365-71.
PMID: 24123004

Andrographolide (Andro) is a diterpenoid that is isolated from Andrographis paniculata and reported to be active against several cancer cell lines. However, few in-depth studies have been carried out on its effects on ovarian cancer cell lines alone or in combination with cisplatin (Cis), which is commonly used to treat ovarian cancer. The aim of this study was to determine the anti-proliferative and apoptotic effects of Andro administered alone and in combination with Cis in the ovarian A2780 and A2780(cisR) cancer cell lines using five different sequences of administration (Cis/Andro h): 0/0h, 4/0 h, 0/4 h, 24/0 h and 0/24 h. The results were evaluated in terms of medium-effect dose (Dm) and combination indices (CI) using the CalcuSyn software. Unlike Cis, whose activity was lower in the resistant A2780(cisR) cell line than in the parent A2780 cell line, Andro was found to be three times more active in the A2780(cisR) cell line as compared to that in A2780 cell line. Synergism was observed when Cis and Andro were administered using the sequences 0/4 h and 4/0 h. The percentage of apoptotic cell death was found to be greater for the 0/4 h combination of Andro and Cis as compared to those values from single-drug treatments. The results may be clinically significant if confirmed in vivo.

Matched MeSH terms: Ovarian Neoplasms
Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

Jim HS, Lin HY, Tyrer JP, Lawrenson K, Dennis J, Chornokur G, et al.

J Genet Genome Res, 2015 09 15;2(2).
PMID: 26807442

Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.

Matched MeSH terms: Ovarian Neoplasms
Radical hysterectomy and pelvic lymphadenectomy for early invasive cancer of the cervix - 14-year experience

Sivanesaratnam V, Sen DK, Jayalakshmi P, Ong G

Int. J. Gynecol. Cancer, 1993 Jul;3(4):231-238.
PMID: 11578351

During a 14-year period, 397 radical hysterectomies and pelvic lymphadenectomies were performed for early invasive carcinoma of the cervix. Twenty-one patients were in stage IA2 with lymphatic/vascular channel permeation (5.2%), 340 in stage IB (85.6%) and 34 in early stage 2A disease (8.5%). Eighteen patients (4.5%) were pregnant. Adenocarcinoma comprised 26.9% of cases. The mean operative time was 4.14 h; the intraoperative blood loss was less than 1.51 in 77.3% patients. There was no operative mortality; one patient died 3 weeks after surgery from clostridium difficile enterocilitis. Eleven patients (2.7%) developed venous thrombosis; severe lymphedema occurred in four (1%). The incidence of uretero-vaginal fistula was 0.2% and that of vesico-vaginal fistula 0.5%. Ovarian metastases were noted in 4.3% of cases with adenocarcinoma. Sixty-six patients had positive nodes (16.6%). Five-year survival in patients with more than 2 positive nodes was 68%. The use of adjuvant chemotherapy in patients with 'high risk' factors resulted in survival rates approaching those without risk factors. Neo-adjuvant chemotherapy was used in 10 patients with large bulky tumors; the results were favorable. Recurrences occurred in 47 patients (11.8%); 36 patients have died (9.1%). Age did not appear to influence survival. The overall 5-year survival was 92.2%.

Matched MeSH terms: Ovarian Neoplasms
Fulltext Molecular Docking Study of Naturally Derived Flavonoids with Antiapoptotic BCL-2 and BCL-XL Proteins toward Ovarian Cancer Treatment

Abd Ghani MF, Othman R, Nordin N

J Pharm Bioallied Sci, 2020 Nov;12(Suppl 2):S676-S680.
PMID: 33828360 DOI: 10.4103/jpbs.JPBS_272_19

The naturally derived flavonoids are well known to have anticarcinogenic effects. Flavonoids could be an alternative strategy for ovarian cancer treatment, due to existing platinum-based drugs are reported to develop resistance with low survival rates. Inhibition of antiapoptotic proteins, namely B-cell lymphoma (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl), is the key target to stimulate apoptosis process in cancer cells. This study aimed to determine the binding interaction of five naturally derived flavonoids (biochanin A, myricetin, apigenin, galangin, and fisetin) with potential antiapoptotic target proteins (Bcl-2 and Bcl-xl). The molecular docking study was conducted using AutoDock Vina program. The binding affinity and the presence of hydrogen bonds between the flavonoids and target proteins were predicted. Our findings showed that all the flavonoids showed better binding affinity with Bcl-xl than that of Bcl-2 proteins. The highest binding affinity was recorded in fisetin-Bcl-xl protein complex (-8.8 kcal/mol). Meanwhile, the other flavonoids docked with Bcl-xl protein showed binding affinities, ranging from -8.0 to -8.6 kcal/mol. A total of four hydrogen bonds, four hydrophobic contacts, and one electrostatic interaction were detected in the docked fisetin-Bcl-xl complex, explaining its high binding affinity with Bcl-xl. The present results indicate that all flavonoids could potentially serve as Bcl-xl protein inhibitors, which would consequently lead to apoptotic process in ovarian cancers.

Matched MeSH terms: Ovarian Neoplasms
Fulltext Diagnosis and Management of Ovarian Cancer: Current Status and Future Potential

Pei, Yin Kang, Ho, Shuyan

Borneo Journal of Medical Sciences, 2019;13(2):49-54.
MyJurnal

Ovarian carcinoma is the fifth common cause of cancer death among women in Malaysia, with five-year survival rates of 30%. It has been associated with delayed diagnosis, advanced stage of presentation and poor prognosis due to vague symptoms and lack of effective screening. The continued high fatality rate has underpinned efforts to develop effective screening tests and newer therapies that could impact on prognosis. New insights into proteomic analysis and genomic tests with a better understanding of the target lesion have leading to discovery of new treatment modalities in ovarian carcinoma. We present a 58-year-old lady with Stage IV ovarian cancer who had lower abdominal pain and mass, constipation and voiding frequency for six months duration. Ultrasound guided biopsy revealed serous adenocarcinoma likely ovarian in origin. CT scan showed gross ascites and right ovarian mass with infiltration to adjacent small bowel. Tumour markers CA 125 and LDH were high. She has received neoadjuvant chemotherapy followed by cytoreductive surgery and currently in remission.

Matched MeSH terms: Ovarian Neoplasms
Fulltext The eyes do not see what the mind does not know: an underreported feature in mature cystic teratoma of the ovary

Wong, Y.P., Tan, G.C.

Medicine & Health, 2018;13(2):223-228.
MyJurnal

Mature cystic teratoma is the commonest ovarian germ cell tumour which accounts for 70% of all benign ovarian neoplasms in the reproductive age groups. Being a pluripotent germ cell tumour, mature cystic teratoma has at least two out of three mature embryonic germ cell components: ectoderm, mesoderm and endoderm. The presence of multiple cystic spaces within the tumour wall, also known as pneumatosis cystoides-like appearance is rarely described but a characteristic feature in cystic teratoma of the ovary. Currently, there is little information concerning the mechanism of its formation. Herein, we described an unusual case of ovarian mature cystic teratoma in a 31-year-old pregnant female with multiple sieve-like areas resembling pneumatosis cystoides of the intestine. Macroscopic and histological examination of the ovary revealed features diagnostic of mature cystic teratoma. Intriguingly, multiple cystic spaces of variable sizes were found within the cyst wall histologically. They were lined partially or completely by foamy histiocytes and foreign body type multinucleated giant cells, exhibiting strong CD68 immunoreactivity. Vascular endothelial markers (CD31 and CD34) and epithelial marker (cytokeratin AE1/AE3) were negative. A diagnosis of mature cystic teratoma with pneumatosis cystoides-like feature was rendered. The patient was discharged well with no signs and symptoms of early labour. The etiopathogenesis of this intriguing histological feature is briefly discussed in this article.

Matched MeSH terms: Ovarian Neoplasms
Fulltext A cytotoxicity and sub-acute toxicity study on tea leaves cultivated in Sabah

Nor Qhairul Izzreen, M. N., Mohd Fadzelly, A. B., Umi Hartina, M. R., Rabiatul Amirah, R., Rozzamri, A.

International Food Research Journal, 2020;27(5):925-933.
MyJurnal

The present work investigated the cytotoxicity capacity of the MDA-MB-231 (human
cancer-derived), A549 (human lung cancer-derived), Caov3 (human ovarian cancer-derived),
and HeLa (human cervical cancer-derived) cell lines on a wide range of tea leaves; green tea,
black tea, tea waste, and compost from Sabah. A group of male and female Sprague Dawley
rats was used to screen the sub-acute toxicity of green tea extract in tea leaves from Sabah for
28 d. Results revealed that the ethanol extract of tea leaves had strong cytotoxic activity
against all cancer lines. Tea waste showed higher cytotoxicity when extracted using hot water.
The ethanol extract of black tea leaves exhibited the highest inhibitory activity against the
proliferation of Caov3, whereas the ethanol extract of green tea leaves exhibited a promising
cytotoxic activity against MDA-MB-231 and HeLa cell lines. Toxicity studies showed
decreased testes weight and increased liver weight in male rats that were administered with
5000 mg/kg of tea extract. This coincided with the significant increase portrayed by enzyme
alanine aminotransferase (ALT) in the serum of treated male rats in the 5000 mg/kg dose
group. Moreover, there was an increase of alkaline phosphatase (ALP) and ALT for the
female rats in the 5000 mg/kg dose group. The increased levels of ALT and ALP enzymes, as
well as liver weight, signified mechanical trauma in the liver of male and female rats in the
5000 mg/kg dose group.

Matched MeSH terms: Ovarian Neoplasms
Fulltext Antioxidant and cytotoxicity effect of rice bran phytic acid as an anticancer agent on ovarian, breast and liver cancer cell lines

Norhaizan ME, Ng SK, Norashareena MS, Abdah MA

Malays J Nutr, 2011 Dec;17(3):367-75.
PMID: 22655458 MyJurnal

Phytic acid (PA) has been shown to have positive nutritional benefits. There are also claims that it is able to prevent cancer through its antioxidant capability. This study investigated antioxidant activity and cytotoxic effect of PA extracted from rice bran against selected cancer cell lines (i.e. ovarian, breast and liver cancer).

Matched MeSH terms: Ovarian Neoplasms
Fulltext Atypical Pelvic Inflammatory Disease (PID) with Empyema and Ascites in A Single Unmarried Lady

Roszaman Ramli, Mokhtar Awang, Ghazali Ismail

International Medical Journal Malaysia, 2006;5(2):1-7.
MyJurnal

Pelvic inflammatory disease (PID) is a common cause of morbidity and accounts for 1 in 60 GP consultations by women under the age of 45 in the UK. Pelvic inflammatory disease encompases a broad category of disease including endometritis, salphingitis, salphingo-oopheritis, tuboovarian abscess and pelvic peritonitis. It most commonly occurs as a result of Chlamydia trachomatis or Nesseria gonorrhea 1,2 infection of the endocervix that eventually spread into the upper genital tract. Direct spread from a nearby infection such as appendicitis and diverticulitis is not that common. Hematogenous spread is rare except in cases of tuberculous pelvic inflammatory disease. This case illustrates atypical presentation of pelvic inflammatory disease in a previously healthy single unmarried lady. The presence of ascites, bilateral ovarian mass and constitutional symptoms closely mimics that of malignant ovarian tumour. This was preceded by empyema which grew E coli.

Matched MeSH terms: Ovarian Neoplasms
Fulltext Antioxidant properties and antiproliferative effect of brewers’ rice extract (temukut) on selected cancer cell lines

Tan, B.L., Suhaniza, H.J., Lai, C. C., Norazalina, S., Roselina, K., Norhaizan, M.E.

International Food Research Journal, 2013;20(5):2117-2124.
MyJurnal

Temukut, or brewers’ rice, is a mixture of broken rice, rice bran, and rice germ. Extensive studies have been conducted on rice bran, which possesses various health benefits. Temukut, however has been less well studied. The present study aimed to investigate the antioxidant and growth inhibition properties of temukut extract using colon cancer (HT-29), ovary cancer (Caov-3), and liver cancer (HepG2) cell lines. The antioxidant activity was determined by the β-carotene bleaching assay, analysis of the DPPH radical scavenging capacity, and a FRAP assay. The total phenolic compounds, oryzanol, vitamin E, and phytic acid levels in temukut were also investigated. The antiproliferative activity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. There was a significant difference in the cytotoxicity of two types of temukut extract (water and methanol) for HT-29 and Caov-3 cells (p < 0.05) but not for HepG2 cells. The HepG2 cell line is the least sensitive to temukut, (IC50 = 55.30 μg/mL), whereas the highest sensitivity was observed in Caov-3 cells (IC50 =36.67 μg/mL). No cytotoxic effect of temukut was observed on normal cells (BalBlc3T3). Although the content of the phytochemicals studied (total phenolic compounds, vitamin E, oryzanol, and phytic acid) in temukut was lower than that in rice bran, as has been previously reported, the present study demonstrated temukut’s potential to inhibit the proliferation of HT-29, Caov-3, and HepG2 cells.

Matched MeSH terms: Ovarian Neoplasms
Fulltext One stop centre staging by contrast-enhanced 18F-FDG PET/CT in preoperative assessment of ovarian cancer and proposed diagnostic imaging algorithm: a single centre experience in Malaysia

Subapriya Suppiah, Andi Anggeriana Andi Asri, Fathinul Fikri Ahmad Saad, Hasyma Abu Hassan, Norhafizah Mohtarrudin, Chang, Wing Liong, et al.

Malaysian Journal of Medicine and Health Sciences, 2017;13(2):29-37.
MyJurnal

Introduction: Suspicious adnexal masses need to be investigated thoroughly as it may represent ovarian cancer, which is the fourth most common gynaecological cancer in Malaysia. Conventional cross sectional imaging may reveal non-specific findings, thus lead to unnecessary biopsies. 18F-Fluorodeoxyglucose positron emission tomography/ computed tomography (18F-FDG PET/CT) has emerged as a useful tool, for characterization of indeterminate adnexal masses. Most studies have been conducted in Western population, and little information is available in Asian population in general and Malaysian population in particular. Methods: Prospective study of women with suspicious adnexal masses, referred to the Centre for Nuclear Diagnostic Imaging, Universiti Putra Malaysia to undergo pre-operative whole-body contrast-enhanced 18F-FDG PET/CT scans from January 2014 to January 2016. Subjects underwent Contrast-Enhanced Computed Tomography (CECT) scans followed by positron emission tomography (PET) scans using a hybrid scanner. Two radiologists analyzed the CECT and PET/CT images by consensus; blinded to the HPE results. Then the PET/CT findings were correlated with HPE results as the gold standard. Results: 11 whole-body PET/CT scans and 18 adnexal masses (12 HPE-proven malignant lesions and 6 benign lesions) were analyzed. The sensitivity, specificity, PPV, and NPV of CECT alone compared to PET/CT was 91.7%, 50.0%, 78.6%, and 75.0% vs. 91.7%, 100%, 100% and 85.7% respectively. Conclusions: Improved diagnostic accuracy for characterizing benign and malignant adnexal masses can be achieved using contrast-enhanced 18F-FDG PET/CT, making it a potential investigation of choice which can help in treatment planning.

Matched MeSH terms: Ovarian Neoplasms
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: Ovarian Neoplasms/genetics; Ovarian Neoplasms/metabolism; Ovarian Neoplasms/pathology
Fulltext Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Kuchenbaecker KB, Ramus SJ, Tyrer J, Lee A, Shen HC, Beesley J, et al.

Nat Genet, 2015 Feb;47(2):164-71.
PMID: 25581431 DOI: 10.1038/ng.3185

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Matched MeSH terms: Ovarian Neoplasms/genetics*
Lectin-based electrophoretic analysis of the expression of the 35 kDa inter-alpha-trypsin inhibitor heavy chain H4 fragment in sera of patients with five different malignancies

Mohamed E, Abdul-Rahman PS, Doustjalali SR, Chen Y, Lim BK, Omar SZ, et al.

Electrophoresis, 2008 Jun;29(12):2645-50.
PMID: 18494030 DOI: 10.1002/elps.200700828

A 35 kDa glycoprotein whose abundance was previously demonstrated to be enhanced in sera of patients with endometrial adenocarcinoma (n = 12), was isolated from pooled sera of three of the cancer patients using champedak galactose-binding lectin affinity chromatography in the present study. Subjecting it to 2-DE and MS/MS, the glycoprotein was identified as the O-glycosylated fragment of inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4). When compared to control sera (n = 17), expression of the 35 kDa ITIH4 cleavage fragment was demonstrated to be significantly enhanced in sera of patients with breast carcinoma (n = 10), epithelial ovarian carcinoma (n = 10), and germ cell ovarian carcinoma (n = 10) but not in patients with nasopharyngeal carcinoma (n = 13) and osteosarcoma (n = 7). The lectin-based electrophoretic bioanalytical method adopted in the present study may be used to assess the physiological relevance of ITIH4 fragmentation and its correlation with different malignancies, their stages and progression.

Matched MeSH terms: Ovarian Neoplasms/metabolism
Fulltext Cancer in Sabah (Borneo) a prelimanry survey

Muir CS, Evans MD, Roche PJ

Br. J. Cancer, 1968 Dec;22(4):637-45.
PMID: 5705133 DOI: 10.1038/bjc.1968.75
Matched MeSH terms: Ovarian Neoplasms/epidemiology
Evaluation of germline BRCA1 and BRCA2 mutations in a multi-ethnic Asian cohort of ovarian cancer patients

Hasmad HN, Lai KN, Wen WX, Park DJ, Nguyen-Dumont T, Kang PCE, et al.

Gynecol Oncol, 2016 05;141(2):318-322.
PMID: 26541979 DOI: 10.1016/j.ygyno.2015.11.001

OBJECTIVE: Despite the discovery of breast and ovarian cancer predisposition genes BRCA1 and BRCA2 more than two decades ago, almost all the available data relate to women of European ancestry, with only a handful of studies in Asian populations. In this study, we determined the frequency of germline alterations in BRCA1 and BRCA2 in ovarian cancer patients from a multi-ethnic cross-sectional cohort of Asian ovarian cancer patients from Malaysia.
METHODS: From October 2008 to February 2015, we established a hospital-based cohort of ovarian cancer patients and the germline status of all 218 women with invasive epithelial ovarian cancer was tested using targeted amplification and sequencing of the intron-exon junctions and exonic sequences of BRCA1, BRCA2, PALB2 and TP53.
RESULTS: BRCA1 and BRCA2 mutations were found in 8% (17 cases) and 3% (7 cases) of the ovarian cancer patients, respectively. Mutation carriers were diagnosed at a similar age to non-carriers, but were more likely to be Indian, have serous ovarian cancer, and have more relatives with breast or ovarian cancer. Nonetheless, 42% (10/24) of mutation carriers did not have any family history of breast or ovarian cancer and offering genetic counselling and genetic testing only to women with family history would mean that 35% (6/17) of BRCA1 mutation carriers and 57% (4/7) of BRCA2 mutation carriers would not be offered genetic testing.
CONCLUSIONS: Our data suggest that, similar to Caucasians, a significant proportion of Asian ovarian cancer was attributed to germline mutations in BRCA1 and to a lesser extent in BRCA2.

Matched MeSH terms: Ovarian Neoplasms/genetics*

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