Indonesian Journal of Cancer Chemoprevention

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ISSN / EISSN : 2088-0197 / 2355-8989
Total articles ≅ 210
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Dicky Rizky Febrian, Joko Setyono, Muhamad Salman Fareza, Nur Amalia Choironi, Arif Fadlan, Sarmoko Sarmoko
Indonesian Journal of Cancer Chemoprevention, Volume 12, pp 161-169;

Breast cancer is a second deadly cancer after lung cancer worldwide. Progression of cancer is driven by mutated cancer drive gene such as ARHGAP35. This study aims to analyze the role of ARHGAP35 in the growth and development of breast cancer cells. ARHGAP35 expression level was analyzed using Oncomine (p-value<1E-4; gene rank top 10%). Overall survival (OS) and disease-free survival (DFS) were evaluated by using GEPIA (median cutoff; HR displayed with 95% CI). STRING was used for analyzing the protein-protein interaction network, while WEBGESTALT for KEGG pathway and gene ontology (GO) of ARHGAP35 and associated proteins and cBioPortal for gene mutation. ARHGAP35 was overexpressed in several types of breast cancer, namely invasive ductal breast carcinoma (IDC), invasive ductal and lobular breast carcinoma (IDLC), invasive lobular breast carcinoma (ILC), male breast carcinoma, and mixed ductal and lobular carcinoma (MDLC). High expression of ARHGAP35 had significantly lower OS (p=0.045) compared to low expression of ARHGAP35 and the difference in DFS was not significant (p=0.98). ARHGAP35 interacted with RHOA, RHOB, RHOC, RHOD, RASA1, RND1, RAC1, CDC42, FYN and SRC. KEGG pathway and GO analysis showed that these proteins are highly involved in actin-based processes through adherent junction, axon guidance, focal adhesion, regulation of actin cytoskeleton, and tight junction. Mutation rate analysis showed 34 missense, 29 truncating, 3 fusion, and 1 in frame on ARHGAP35. Taken together, ARHGAP35 may involve in the growth and development of breast cancer through regulation of actin cytoskeleton pathway. Keywords:ARHGAP35, breast cancer, KEGG pathway, mutation rate, actin cytoskeleton.
Bayu Anggoro, Dennaya Kumara, Dhella Angelina, Muthi Ikawati
Indonesian Journal of Cancer Chemoprevention, Volume 12, pp 114-122;

Citrus flavonoids have been known for their vast biological activities including chemoprevention activities. However, the organic solvent extraction system limits its potential utilization. We recently adopted a hydrodynamic-cavitation method to extract citrus flavonoids from citrus peels. In this study we verified the high flavonoid content of the hydrodynamic-cavitation extract from Citrus reticulata peels and explore the potency of its citrus flavonoid contents as targeted chemoprevention agent for breast cancer by using bioinformatics. Based on a thin layer chromatography, the extract positively yielded high content of citrus flavonoids represented by hesperidin. The toxicity analysis by Protox II Online Tool revealed that hesperidin as the major citrus flavonoid in the extract was considered safe with a predicted LD50 of 12,000 mg/kg. We then further exploring citrus flavonoids’ capacity in targeting MAP1LC3A, a key protein in autophagy. UALCAN analysis validated that low expression of MAP1LC3A is associated with low survival rates in breast cancer patients. Limonin, hesperidin, narirutin, neohesperidine, and naringin are flavonoids from citrus peels that predicted to have inhibitory activity against Protein Kinase A (PKA), a negative upstream of MAP1LC3A, calculated by KNIME. Citrus flavonoids scoparone, cirsimaritin, 4',5,7-trimethoxyflavone, eupatorine, and hesperidin were also exhibit similar structure to an agonist of ATG4B, a protein that plays a role in MAP1LC3A activation. Furthermore, eupatorine, hesperidin, and cirsimaritin displayed a high affinity to ATG4B based on a molecular docking. We concluded that citrus flavonoids from citrus peels are safe to normal cells, and the citrus flavonoids potentially targets MAP1LC3A by inhibiting PKA and acting as ATG4B agonists. Thus, this extract-contained flavonoids from citrus peels is potential to be investigated further as a chemoprevention agent by inducing autophagy, especially for breast cancer. Keywords:Citrus reticulata, citrus flavonoid, autophagy, MAP1LC3A, breast cancer.
Ratih Kurnia Wardani, I Made Rhamandana, Christina Mutiara Putri Gono, Muthi Ikawati
Indonesian Journal of Cancer Chemoprevention, Volume 12, pp 137-147;

Overexpression of geranylgeranyl diphosphate synthase 1 (GGPS1) is an unfavorable prognosis in liver cancer development. The side effects of therapeutic standards encourage the development of therapeutic agents from herbal materials. Citrus peels are rich of phytochemical compounds, especially citrus flavonoids, that possess cytotoxic activities. This study aimed to determine the potential of citrus flavonoids as chemopreventive agents targeting GGPS1 protein by phytochemical and bioinformatic studies. Dried peels of Citrus reticulata were extracted by hydrodynamic-cavitation method followed by identification of compounds using thin layer chromatography (TLC). The expression level of GGPS1 was obtained from UALCAN, while its correlation with survival rate was obtained from the GEPIA. Prediction models regarding the potential inhibitors of citrus peel compounds against GGPS1 were obtained through KNIME and ChEMBl, followed by literature studies on chemopreventive activity of citrus flavonoids. The molecular docking was used to predict the molecular interaction followed by tracking of target genes that were positively correlated with GGPS1 by SwissTargetPrediction. Yielded 75% (v/v), the extract positively contained citrus flavonoid with hesperidin as comparison. Overexpression of GGPS1 significantly reduced the survival rate of liver cancer patients (p value=0.019). Four citrus flavonoid compounds, namely tangeretin, nobiletin, hesperidin, and naringenin showed potential inhibition to GGPS1. The molecular docking showed that tangeretin had a strong affinity compared to the native ligand and zoledronic acid, as positive control. PARP1, CSNK2A1, TNKS2, and GSK3B were clarified as targeted genes for tangeretin and nobiletin that positively correlated with GPPS1. In vitro and in vivo studies will validate our findings and support the development of citrus peel extract with rich flavonoid contents as a chemopreventive agent. Keywords:geranylgeranyl diphosphate synthase 1 (GGPS1), liver cancer, hydrodynamic-cavitation, citrus flavonoid, bioinformatic.
Sri Handayani, Dina Aprilia, Khoirun Nisa, Vita Taufika Rosyida, Martha Purnami Wulanjati, Anjar Windarsih, Cici Darsih, Andri Frediansyah, Sari Haryanti
Indonesian Journal of Cancer Chemoprevention, Volume 12, pp 170-179;

Protective agent for hepatotoxicity is still a great challenge in the management of liver diseases. Aloe vera is a beneficial plant that has been studied for food supplements, cosmetic and herbal medicine. Aloe vera contains many compounds which have a role in body health including polysaccharides, phenolic, flavonoid, terpenoid, amino acid, and several minerals. There have been compelling evidences that natural phytochemicals and their derivatives have hepatoprotective activities. Information of the aloe vera and its mechanism of action for possible hepatoprotective activities, including in silico, in vitro, and in vivo studies were obtained from Pubmed, Science Direct, Scopus, and Google scholar search engines. This current review was focusing on the possible contribution of compounds inside aloe vera gel and the suggestion of its mechanism on protective effect, especially for liver. The complexity of monosaccharides composition, backbone structures, acetyl group, and molecular weight of aloe polysaccharides have possible correlations with its hepatoprotective effect. Most of the hepatoprotective mechanisms of aloe compounds are related to their protective effect against inflammation and oxidative stress. Several compounds may have combination effects or several targets lead to synergistic effects. Keywords:Aloe vera, food supplement, hepatoprotective, liver disease, mechanism of action.
Hamzah Hamzah, Thomas Erwin Christian Junus Huwae, Chodidjah Chodidjah
Indonesian Journal of Cancer Chemoprevention, Volume 12, pp 123-129;

Post-menopausal osteoporosis is a degenerative disease among post-menopausal women. In Indonesia, women over 50 years old get post-menopausal osteoporosis.The therapy should be comprehensive and continous. Bisphosphonate therapy is one of the most preferable therapeutic option for maintaining bone density. Calcium and vitamin D have a role in increasing osteoblastic activity. The objective of this study was to describe the vitamin D and calcium in bone mineral density (BMD) of hip and spine in postmenopausal woman with biphosphonat therapy. This study is a cross-sectional, observational analytic. The subject were female patients with post-menopausal osteoporosis treated in clinic of RSUD dr. Saiful Anwar Malang, who had received routine bisphosphonate for at least 1 year. The method was collecting the patient data, who received oral and injectie bisphosphonate therapy, serial BMD test,hip and spine, vitamin D and calcium level in serum test. Total sample 25 participan, the association between BMD change (Δ BMD), vitamin D and calcium level, were analyzed.with Chi Square test then continued using Spearman correlation test. Vitamin D levels in Δ BMD Spine in participants was less <30 ng/ml, mean 16.8+6.95 14 respondents (56%), and 6 respondens (24%) 10.05+5.28, normal vitamin D levels were 5 respondents (20%) mean 34.16+5.10. Vitamin D levels in Δ BMD Hip in participants was less <30 ng/ml, mean 15.19+7.7 12 respondents (48%), and 8 respondens (32%) 12.30+5.57, normal vitamin D levels were 5 respondents (20%) 33.66+5.40. Calcium levels in BMD spine 9.60+0.45, 14 respondents (56%), and 11 respondens (44%) 9.59+0.52. There is a significant and moderate relationship between vitamin D levels with Δ BMD spine (p=0.009, r=0.564) and Hip (p=0.039, r= 0.480) T Blood calcium levels with Δ BMD changes unrelated (normal). There is a significant association between vitamin D levels spine and Hip Δ BMD. Blood calcium levels with Δ BMD changes unrelated. Keywords:Osteoporosis, Bisphosphonate, Vitamin D levels, Calcium levels.
Sri Susilowati, Neni Susilaningsih, Catharina Suharti
Indonesian Journal of Cancer Chemoprevention, Volume 12, pp 130-136;

Apoptosis is one of the anticancer targets. Currently, the concomitant use of phytotherapy products and chemotherapy regimens is common in breast cancer patients. The purpose of this study was to examine the apoptotic effect of adding beetroot extract to the neoadjuvant Adriamycin Cyclophosphamide (AC) regimen by observing the expression levels of p53 and caspase 3 in tumor tissue from mammary adenocarcinoma rats. Twenty-four rats that succeeded in growing tumor nodules were randomly divided into 4 treatment groups: without treatment, AC only treatment, AC plus beetroot extract at dose of 25 and 100 mg/kg BW, respectively. AC was given 4 cycles in doses of 5 and 50 mg/kg body weight intraperitoneally every week. Tumor tissue was dissected at 4th week for examination of p53 and caspase 3 expression levels using the qRT-PCR method. The addition of beetroot extract at doses of 25 and 100 mg/kg BW in the neoadjuvant AC regimen showed significantly higher levels of p53 and caspase 3 expression than those with AC treatment alone. These results proved that beetroot extract has a synergistic effect with neoadjuvant AC regimen by increasing tumor cells apoptosis. Keywords:Beetroot extract, Adriamycin, Cyclophosphamide, apoptosis, p53.
Roihatul Mutiah, Tanaya Jati Dharma Dewi, Arief Suryadinata, Kesimira Qonita
Indonesian Journal of Cancer Chemoprevention, Volume 12, pp 148-160;

Citrus maxima or pomelo is a plant that has potential as an anticancer because it contains flavonoids. One of the targets of breast anticancer receptors is the HER-2 protein. This research aims to determine the anticancer activity, the toxicity of the compound, and the prediction of physicochemical properties of flavonoids contained in Citrus maxima through in silico approach. Flavonoid compounds were screened using SwissADME with Lipinski's rule of five, Torsion, TPSA, and P-Gp Non-Substrate. Compounds that passed the screening were carried out molecular docking to the HER-2 receptor (PDB ID: 3PP0) using the Molegro Virtual Docker (MVD). The HER-2 receptor (GDP ID: 3PP0) was declared valid because it had RMSD<2Å. The results showed that there were 11 flavonoid compounds that passed the screening and had a lower rerank score than the comparison compound Trastuzumab. Toxicity was predicted using the Protox II online tool and the results showed that the flavonoid compounds were in the safe limits, namely classes 5 and 3. Based on this research, it can be concluded that acacetin, diosmetin, honyucitrin, isosinensetin, nobiletin, sinensetin, and tangeretin can be candidates for breast cancer drugs based on natural ingredients. Keywords:breast cancer, Citrus maxima, HER-2, in silico.
Dyaningtyas Dewi Pamungkas Putri, Erina Rivanti, Raditya Prima Istiaji, Edy Meiyanto
Indonesian Journal of Cancer Chemoprevention, Volume 12, pp 67-73;

Leunca (Solanum nigrum L.) is a potential source of natural anticancer agents. Solanum nigrum L. ethanolic extract (SNE) has cytotoxic activity in several cancer cell lines. We aimed to evaluate the ability of SNE to increase MCF-7 cell sensitivity to doxorubicin as a chemotherapeutic agent for breast cancer. Cell viability of SNE and its combination treatment with doxorubicin were conducted by 3-(4,5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide (MTT) assay, and apoptosis assay was analyzed by Ethidium bromide-acridine orange method. The SNE showed a cytotoxic effect in the MCF-7 cell line with IC50 50 μg/mL. Combination treated DOX-SNE resulted in a combination index (CI) value of 0.21, indicating strong synergism SNE and doxorubicin. The SNE 25 μg/mL combined with doxorubicin 100 nM optimally induced apoptosis of MCF-7 cells. We concluded that SNE is the potential to be developed as a co-chemotherapeutic agent through apoptosis induction though the molecular mechanism need to explore.Keywords: Solanum nigrum L. herb ethanolic extract, doxorubicin, MCF-7, apoptosis.
Pekik Wiji Prasetyaningrum, Endah Puji Septisetyani, Ahmad Suyoko, Adi Santoso
Indonesian Journal of Cancer Chemoprevention, Volume 12, pp 99-105;

The C2C12 myoblasts are adult murine muscle stem cells which isolated after injury to induce muscle regeneration. The cells are widely used in pharmaceutical and biological researches to represent skeletal muscle cells. In our laboratory, we utilize the cells for glucose uptake assay after insulin treatment and studying the muscle regeneration. In this study we conducted recloning of C2C12 cells by limiting dilution cloning (LDC) and investigated the biological properties incuding cell proliferation, adhesion and differentiation of the clonal cells in comparison to the parental cells. Cell proliferation rate had been determined by WST assay, cell adhesion had been observed after cell detachment by EDTA and cell differentiation into multinucleated myotube had been investigated after induction and incubation with horse serum. As results, two clonal derivatives of C2C12 myoblast cells had been retrieved by LDC and used for cell assays. Moreover, the results indicated that parental cells showed faster proliferation rate and better differentiation ability than that of clonal cells. In the contrary the parental cells exhibited weaker adhesion rate than clonal cells. To conclude, C2C12 parental cells are better for performing the glucose uptake or muscle regeneration assays since they showed better differentiation capability.Keywords: C2C12 cells, cells differentiation, myoblast, myotube, recloning.
Roihatul Muti'Ah, Eka Kartini Rahmawati, Tanaya Jati Dhrama Dewi, Alif Firman Firdausy
Indonesian Journal of Cancer Chemoprevention, Volume 12, pp 90-98;

Heliannuols are sesquiterpenes lactone compounds considered to have anticancer activity on the brain cancer. Cancer cell growth is related to overexpression of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) as a pro-angiogenic pathway, which becomes the main factor of angiogenesis and progression. This research aims to predict anti-angiogenic, toxicity, and physicochemical properties of heliannuols. Physicochemical properties were predicted referred to Lipinski’s rule of five (Lipinski RO5), while absorption, distribution, metabolism, and excretion were predicted by using pkCSM online tool. The toxicity of compounds was predicted by using Protox II online tool, and interaction of the ligand with receptors was predicted by conducting validation (VEGFR-2 (PDB ID: 3WZE)) and molecular docking using Molegro Virtual Docker (MVD). The result revealed that Lipinski RO5 compatible heliannuols had the lowest LD50 2148 mg/kg predictive LD50 predictive values of heliannuol D. The docking result was described by rerank score (RS), representing the bound energy form and compares with Sorafenib as a reference drug. Five medium strength VEGFR-2 chemical substances with rerank score: heliannuol A -56.9496, heliannuol heliannuol B -70.83646, heliannuol C -61,3292, heliannuol D -49.61646, and heliannuol E -75.5164. No better rerank score was recorded for all inhibitors than sorafenib (-128.0683). The heliannuols interacted with amino acid residues Glu885 and Asp1046 that probably conferred the antiangiogenic activity. Taken together, heliannuol D had the greates activity to the target protein and complied Lipinski RO5.Keywords: anti-angiogenic, toxicity, heliannuol, VEGFR-2, brain cancer, molecular docking.
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