|Year : 2022 | Volume
| Issue : 77 | Page : 175-182
Network pharmacology analysis with molecular docking of phytochemicals of Panax ginseng against osteosarcoma
Fahad Hassan Shah, Song Ja Kim
Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju 32588, Republic of Korea
|Date of Submission||09-Nov-2021|
|Date of Decision||19-Nov-2021|
|Date of Acceptance||24-Dec-2021|
|Date of Web Publication||28-Mar-2022|
Song Ja Kim
Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju
Republic of Korea
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Panax ginseng is a perennial medicinal herb also known as Korean ginseng or Insam (인삼), commonly found in Korean Peninsula. These herbs are used to treat different types of diseases. Recent studies have shown that phytochemicals found in P. ginseng harbor anticancer activity against various cancers. However, the biological and molecular mechanisms of these phytochemicals are still unknown in osteosarcoma (OS). Materials and Methods: This study utilized the network pharmacology method comprised target prediction, gene enrichment and ontology, KEGG pathway analysis, and gene expression studies. The obtained results were used to predict the interaction of phytochemicals with the human CDKL3 domain implicated in OS using molecular docking. Toxicity and pharmacokinetic elements of these phytochemicals were also identified. Results: Results showed that Fumarine and Inermin are bioactive phytochemicals that have a multimodal effect on multiple targets and pathways involved in the progression of OS. These compounds were able to regulate the expression of genes and interacted with human CDKL3. These compounds have good pharmacokinetic and toxicological characteristics. However, they exert a high risk of hepatotoxicity. Conclusion: The present study provided a predicted mechanism of action of bioactive phytochemicals of P. ginseng in the inhibition of OS.
Keywords: Fumarine, inermin, molecular docking, network pharmacology, osteosarcoma, Panax ginseng, pharmacokinetics, toxicity
|How to cite this article:|
Shah FH, Kim SJ. Network pharmacology analysis with molecular docking of phytochemicals of Panax ginseng against osteosarcoma. Phcog Mag 2022;18:175-82
|How to cite this URL:|
Shah FH, Kim SJ. Network pharmacology analysis with molecular docking of phytochemicals of Panax ginseng against osteosarcoma. Phcog Mag [serial online] 2022 [cited 2022 Sep 30];18:175-82. Available from: http://www.phcog.com/text.asp?2022/18/77/175/341078
- The phytochemicals contained in the P. ginseng has been explored in the treatment of osteosarcoma (OS) using Network Pharmacology method
- Drug likeness and pharmacokinetic screening identified six potential medicinal compounds such as Fumarine, Inermin, Frutinone A, Celabenzine, Nepetin and Suchilactone
- Fumarine and Inermin showed moderate anti-OS activity identified by Network Pharmacological analysis
- Molecular docking validation was reconfirmed that Fumarine and Inermin are potential candidate for the treatment of OS.
Abbreviations used: ADMET: absorption, distribution, metabolism, excretion and toxicity, BATMAN-TCM: Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine, BBB: Blood Brain Barrier, CDKL3:Cyclin dependent kinase like 3, KEGG: Kyoto Encyclopedia of Genes and Genomes, OS: Osteosarcoma, PASS: Prediction of activity spectra for biologically active substances, P. ginseng: Panax ginseng, TCMSP: Traditional Chinese Medicine System Pharmacology Database, TTD: Therapeutic Target Database.
| Introduction|| |
Osteosarcoma (OS) is a primary skeletal tumor in which aberration in the bone-forming mesenchymal cells causing the formation of an immature osteoid matrix. This type of tumor has a high malignancy rate and usually originates in soft tissues. An approximate incidence of OS reported around ~4 million cases per year in adults, whereas ~5 million cases per year in children (0–19 years). The disease etiology is still elusive yet; however, some studies indicated that exposure to radiation initiates OS formation reported in 2% of cases. However, it has been largely attributed to germline mutation in p53 protein.
OS is characterized as surface and central bone tumors classified by the World Health Organization system of histological classification. Almost 90% of OS cases are diagnosed as central tumors. The musculoskeletal tumor society has devised a staging system (I-III) to observe and characterize the tumor progression. Stage I and II are low-grade tumors, whereas Stage III are highly malignant and vulnerable to metastasis. The therapy for OS is comprised of surgery, in which amputation of the affected limb is performed combined with post-therapy chemotherapy. However, in high-grade tumors, the treatment fails to avert the proliferation and expansion of OS. Another arising issue with this tumor is the development of resistance to chemotherapy which makes it more challenging to avert the recurrence and metastasis.,, That is due to the involvement of multiple protein factors facilitating such processes. So far, no targeted treatments have been discovered for this disease to prolong the survival rate. The discovery of new therapeutic molecules able to perform multiple biological activities, including anticancer with anti-metastatic properties is of great concern to be able to deter cancer growth and development. Network pharmacology is defined as an integration of system biology, network analysis, and in silico drug discovery methods to determine the multiple pharmacological activities of a compound against various diseases., This method combined with medicinal phytochemicals can be beneficial to discover therapeutic with biological activity against multiple targets in the studied disease.
In our study, we used the network pharmacology method to explore the phytochemicals of Panax ginseng against OS. P. ginseng is an ethnobotanical plant of the Korean Peninsula and China that belongs to the family of Araliaceae, Genus: Panax L, and Species: P. ginseng Meyer. Traditionally, the dried form of the plant, especially the roots, has been used to treat several diseases, including cancer and inflammation. Recently, these plants have been utilized to extract various bioactive compounds whose biological activity is yet to be determined. The present study obtained all these compounds contained in P. ginseng and explored the activity against OS using network pharmacology combined with in silico interaction studies.
| Materials and Methods|| |
Selection of bioactive compounds in Panax ginseng
The current study utilized P. ginseng to analyze its therapeutic effect on OS. We have accessed the traditional Chinese medicine (TCM) system pharmacology database, to acquire bioactive compounds from this plant. In the search box, P. ginseng was searched as a keyword, and compounds information related to this plant was downloaded in the excel file. The compounds were selected based on drug-likeness (DL), oral bioavailability (OB), toxicity class, and Lipinski's rule of five.
Screening of target genes
Gene cards database was used to procure gene targets involved in the progression of OS. Bioinformatics Analysis Tool for Molecular mechANism (BATMAN) TCM, and DIGEP-Pred, webservers were accessed to predict the effect of phytochemicals on the target's genes. The canonical SMILES of these compounds were used to retrieve the prediction results of the compound's induced effect on genes.
The compound's interaction was evaluated against human CDKL3 kinase is an important molecular target of OS. This analysis was facilitated by IGEMDOCK, and the compounds were targeted toward the 38R active site of CDKL3. The amino acids residues present in the 38R active site are VAL18, VAL10, LYS33, PHE79, GLU80, ILE82, THR85, GLU129, LEU132, and CYS142. The interaction of compounds with these residues was considered, and interactions other these residues were discarded.
Profiling of toxic characteristics
Toxic characteristics such as acute toxicity dose, organ-specific damage, and adverse effects prediction were predicted with GUSAR, ROSC-Pred, and Adver-Pred database. These characteristics were determined by providing the canonical SMILES of compounds.
PASS and absorption, distribution, metabolism, excretion, and toxicity prediction
Other biological activities and pharmacokinetic attributes absorption, distribution, metabolism, excretion, and toxicity (ADMET) of compounds present in P. ginseng were also determined to explain their possible mechanism of action and safety attributes in the human body. These attributes were predicted by ADMET SAR 2.0, and PASS online.
| Results|| |
Compounds selection in Panax ginseng
TCM database identified 215 medicinal compounds in P. ginseng. The information of these compounds was downloaded and screened for DL, oral BO, toxicity class, and Lipinski's rule of five. Parameters set for obtaining bioactive compounds were: DL >0.3, OB >20%, toxicity class >Class 4, and Lipinski's: no violations. Results of DL and OB were already indicated by TCMSP, but toxicity class and Lipinski's evaluation were facilitated by ProTox-II, and SwissADME. After refinement, six compounds [Table 1] qualified the criteria, which were further used for gene expression, target prediction, biological pathway governed by these targets, and enrichment and ontological analysis along with drug-target network association.
|Table 1: Physiochemical nature of medicinal compounds present in Panax Ginseng|
Click here to view
Network pharmacology analysis
Identification numbers of these compounds were procured from the PubChem database and added to the dialog box of BATMAN-TCM. The score cut off was kept at 15 for target prediction, whereas for target analyses, the adjusted P ≤ 0.05. In [Table 2], Fumarine (4970) influenced 35 genes, whereas Inermin on 14 genes. Nepetin, Celabenzine, Frutinone A, and Suchilactone had no potential effect on any target [Table 2]. Gene enrichment analysis of these genes showed that seven enriched KEGG pathways (RAS signaling pathway, Rap1 signaling pathway, PI3K-AKT signaling pathway, hematopoietic cell lineage, purine metabolism, cytokine-cytokine, and neuroactive ligand-receptor interaction, respectively) [Table 3]. Significantly enriched therapeutic target database (TTD) diseases regulated by these compounds were analgesics, chronic obstructive pulmonary disease, asthma, OS, ischemia, nausea, and vomiting, cough, dyspnea, B-lineage malignancies, allergic rhinitis, multiple organ failure, acute myelogenous leukemia, chronic urticaria, sustained ventricular tachycardia, chronic myeloproliferative disease, phyllodes tumors, macular edema, and other, as mentioned in [Table 4]. Gene ontological studies revealed that these two compounds have a role in initiating molecular functions such as signal transducer activity, kinase activity, and ion binding, as summarized in [Table 5]. Biological processes include circulatory system process, cellular protein modification process, lipid metabolic process, response to stress, signal transduction, cell-cell signaling, cell proliferation, and differentiation and locomotion, homeostatic process, anatomical structure development, and neurological system process. The compound target pathway/disease network obtained from BATMAN-TCM is illustrated in [Figure 1]. Gene expression induced by these compounds was explored with DIGEP-Pred. It was observed that Fumarine upregulates the CASP2 gene, whereas Inermin downregulated PCOLCE2 and STK39 and upregulated NOTCH1 and GAS6 genes [Table 6].
|Table 4: Enriched therapeutic target database Results of Fumarine and Inermin|
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|Figure 1: Network Pharmacological Analysis of Phytocompounds of Panax ginseng. PubChem 4970 stands for fumarine, PubChem 91510 stands for inermin|
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Molecular docking results
We have discarded Suchilactone, Celabenzine, Nepetin, and Frutinone A from further analysis based on their inactivity in the network pharmacological analysis. Fumarine and Inermin were then used to check the interaction with CDKL3 protein, which is highly upregulated in OS cells and provides them with proliferative properties. The standard docking algorithm of IGEMDOCK was selected, which is comprised a population size of 200, generation: 70, and a number of docked solutions = 3. Site-directed docking was performed, and the results were characterized on hydrogen interaction of compounds with the active site of CDKL3 protein. IGEMDOCK analysis revealed that Fumarine [Figure 2] and Inermin [Figure 3] established hydrogen bonding with LYS33 amino acid of CSKL3 protein, indicating a similar mechanism of action [Table 7].
|Figure 2: Molecular conformation of fumarine interaction with human CDKL3 protein|
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|Figure 3: Molecular conformation of inermin interaction with human CDKL3 protein|
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Toxicity profiling results
Fumarine has acute toxicity of 135,100 mg/kg for the intraperitoneal route, 22,960 mg/kg for the intravenous route, 616,500 mg/kg for the oral route, and 224,800 mg/kg for the subcutaneous route. The acute toxicity dose of Inermin was 237,100 mg/kg for the intraperitoneal route, 56,720 mg/kg for the intravenous route, 1,150,000 mg/kg oral and 306,100 mg/kg subcutaneous routes, respectively. These compounds are characterized as class 4 chemicals and the adverse and organ damaging effects associated with these compounds are given in [Table 8].
PASS and absorption, distribution, metabolism, excretion, and toxicity prediction
The biological function of these compounds was further explored with PASS online. Results indicated that Fumarine stimulates the activity of caspase 8,3 and promotes apoptosis and tumor suppressor gene-53 (TP53) expression. It is also an antineoplastic alkaloid and inhibits topoisomerase-I activity. A similar type of activity was observed for Inermin except for this compound also has topoisomerase-I and topoisomerase-II activity [Table 9]. ADMET SAR 2.0 was used to predict the compound's absorption, site of metabolism, and toxicity. Fumarine has a high blood–brain barrier (BBB) and intestinal absorption and its subcellular localization is lysosome. This compound is inactive against p-glycoprotein, CYP2C9, CYP3A4, and CYP2C9 whereas active for CYP2D6 substrate and inhibit CYP2C19, CYP2D6, and CYP1A2. It is nontoxic to cells and genes but possesses high hepatotoxicity. Inermin has high intestinal and BBB permeability and it is subcellularly localized in mitochondria. Like Fumarine, Inermin also has no activity for p-glycoprotein, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2, respectively [Table 10]. This compound is relatively more toxic than Fumarine.
| Discussion|| |
OS is multifactorial cancer which means this disease requires the activity of various genes to drive the growth of osteoblastic cells. Recent studies emphasized inhibiting a single OS target to prevent tumor proliferation., However, cancer cells have devised various mechanisms to circumvent the inhibited protein target by stimulating other genes to further navigate the pathway to sustain the survival of the tumor., These mechanisms are also responsible for developing resistance, invasiveness, and migratory properties to OS cells. Therefore, single target targeting drugs becomes obsolete considering the complex evading mechanism of this disease. In recent years, network pharmacology has changed drug discovery research by merging artificial intelligence to correlate the interaction of therapeutic drugs with cellular networks and genes. This new discipline allowed researchers to understand the effect of drug interaction with various molecular targets and cellular networks. Natural compounds are constantly being repurposed for different types of diseases. However, these natural compounds are multimodal in action and influence multiple molecular targets which were overlooked previously prior to the discovery of network pharmacology. The emergence of this discipline streamlined the process of drug discovery and allowed scientists to thoroughly evaluate the therapeutic effects of a compound on a biological system.
In this study, we used network pharmacology, in silico gene expression, molecular docking, and ADMET method to elaborately analyze P. ginseng phytocompounds against OS. Initially, we obtained 215 compounds of P. ginseng from TCMSP, which on screening yielded 6 bioactive compounds such as Fumarine, Inermin, Fruitnone A, Celabenzine, Nepetin, and Suchilactone. These compounds were subjected to network pharmacology analysis to unravel their biological activity in OS.
BATMAN-TCM database facilitated the network pharmacology analysis and the results revealed that Fumarine and Inermin had a significant interaction with different biologically active targets, whereas Fruitnone A, Celabenzine, Nepetin, and Suchilactone failed to show any discerning activity. The predicted molecular target targeted by Fumarine was 35 and 13 for Inermin. These gene targets were subjected to gene enrichment studies to establish a significant association with different disease phenotypes and to recognize the molecular functions, cellular locations, and biological processes governed by these compounds. These compounds affect purine metabolism, which allows rapid tumor cell proliferation and growth in OS. Ras, Rap1, and PI3K-AKT signaling pathways, are implicated in providing OS cells with invasive and migratory properties that are also targeted by these compounds. The therapeutic target database showed that these compounds have a significant therapeutic influence in alleviating pain, cancer, and other physiological ailments, including OS. Gene ontological analysis revealed that these compounds have a role in regulating biological and molecular functions along with some cellular functions.
We took these compounds and analyzed them with DIGEP-pred to evaluate the effects on mRNA gene expression, which might have been overlooked BATMAN-TCM algorithm. Fumarine upregulated the expression of the CASP2 gene, which is involved in inducing tumor cell apoptosis. Whereas Inermin reduced the expression of PCOLCE2 and STK39. Both these genes equip OS cells with rapid proliferative, migratory invasiveness, and metastatic properties,, Moreover, this compound upregulates some other regulatory genes that help in the prevention of tumor growth invasiveness and sensitize these cells to chemotherapy.,, From gene ontological analysis, it was observed that these compounds have a role in regulating cell proliferation and kinases activity. To further validate these findings, we used the molecular docking method to analyze the inhibitory effects on CDKL3 kinase which is involved in OS progression and proliferation. These compounds were focused on the reported active site residue of CDKL3 kinase protein to determine the protein-ligand interaction. IGEMDOCK software was used, and the docking studies were performed three times to increase confidence in the obtained results. Both these compounds used the same amino acid residues LYS33 to establish hydrogen bonding with the CDKL3 protein. This interaction shows that Inermin and Fumarine have a similar mechanism of action.
Furthermore, we utilized the PASS algorithm to identify other biological activities. The results of PASS prediction predicted that these compounds stimulate the activity of caspase 3, and 8,, and TP53. These proteins induce tumor apoptosis and prevent tumor recurrence and growth. Besides these activities, they also interact with topoisomerase I and II that provide further evidence that these compounds also prevent DNA replication in OS cells.
The safety and pharmacokinetic properties of a compound is a major component in drug discovery and development. Inadequate elucidation of these properties of a compound can jeopardize human health and may lead to serious harm during a clinical trial. To determine these properties, we elaborately analyzed each compound to increase its approval rating in different animal and clinical trials. These compounds are highly soluble and readily absorbed inside the gastrointestinal tract. However, these compounds pose a significant risk of causing hepatotoxicity and can affect the stomach and liver. These challenges can hinder their therapeutic efficacy and approval in various clinical trials. There are several methods reported in the literature to solve these challenges associated with these compounds, such as nanoformulations, structural modification, organic synthesis, and drug concentration calibration.
| Conclusion|| |
Inermin and Fumarine present in P. ginseng have significant anticancer activity in OS cells. These compounds target both genes and other molecular drug targets to reduce the proliferation and aggressiveness of these tumors. However, the toxic nature of these compounds could jeopardize their therapeutic activity that can be a challenge for other researchers to work on. Our findings provided an elaborate insight about Inermin, and Fumarine in OS treat, which require further in vitro validation.
Financial support and sponsorship
This work was supported by the National Research Foundation of Korea (NRF) funded by the Korean Government (MEST) (2020R1I1A306969912).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Misaghi A, Goldin A, Awad M, Kulidjian AA. Osteosarcoma: A comprehensive review. SICOT J 2018;4:12.
Sadykova LR, Ntekim AI, Muyangwa-Semenova M, Rutland CS, Jeyapalan JN, Blatt N, et al.
Epidemiology and risk factors of osteosarcoma. Cancer Invest 2020;38:259-69.
Picci P. Osteosarcoma (osteogenic sarcoma). Orphanet J Rare Dis 2007;2:6.
Kundu ZS. Classification, imaging, biopsy and staging of osteosarcoma. Indian J Orthop 2014;48:238-46.
] [Full text]
Deng Z, Huang Z, Ding Y, Su Y, Chan CM, Niu X. High-grade surface osteosarcoma: Clinical features and oncologic outcome. J Bone Oncol 2020;23:100288.
Marchandet L, Lallier M, Charrier C, Baud'huin M, Ory B, Lamoureux F. Mechanisms of resistance to conventional therapies for osteosarcoma. Cancers (Basel) 2021;13:683.
Fanelli M, Tavanti E, Patrizio MP, Vella S, Fernandez-Ramos A, Magagnoli F, et al.
Cisplatin resistance in osteosarcoma: In vitro
validation of candidate DNA repair-related therapeutic targets and drugs for tailored treatments. Front Oncol 2020;10:331.
Hattinger CM, Patrizio MP, Fantoni L, Casotti C, Riganti C, Serra M. Drug resistance in osteosarcoma: Emerging biomarkers, therapeutic targets and treatment strategies. Cancers (Basel) 2021;13:2878.
Zhang R, Zhu X, Bai H, Ning K. Network pharmacology databases for traditional chinese medicine: Review and assessment. Front Pharmacol 2019;10:123.
Liu ZH, Sun XB. Network pharmacology: New opportunity for the modernization of traditional Chinese medicine. Yao Xue Xue Bao 2012;47:696-703.
Mancuso C, Santangelo R. Panax ginseng
and Panax quinquefolius
: From pharmacology to toxicology. Food Chem Toxicol 2017;107:362-72.
Liu H, Lu X, Hu Y, Fan X. Chemical constituents of Panax ginseng
and Panax notoginseng
explain why they differ in therapeutic efficacy. Pharmacol Res 2020;161:105263.
Ru J, Li P, Wang J, Zhou W, Li B, Huang C, et al.
TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014;6:13.
Liu Z, Guo F, Wang Y, Li C, Zhang X, Li H, et al.
BATMAN-TCM: A bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine. Sci Rep 2016;6:21146.
Lagunin A, Ivanov S, Rudik A, Filimonov D, Poroikov V. DIGEP-Pred: Web service for in silico
prediction of drug-induced gene expression profiles based on structural formula. Bioinformatics 2013;29:2062-3.
Hsu KC, Chen YF, Lin SR, Yang JM. iGEMDOCK: A graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis. BMC Bioinformatics 2011;12 Suppl 1:S33.
Lagunin A, Zakharov A, Filimonov D, Poroikov V. QSAR modelling of rat acute toxicity on the basis of PASS prediction. Mol Inform 2011;30:241-50.
Lagunin A, Rudik A, Druzhilovsky D, Filimonov D, Poroikov V, Wren J. ROSC-Pred: Web-service for rodent organ-specific carcinogenicity prediction. Bioinformatics 2018;34:710-2.
Ivanov SM, Lagunin AA, Rudik AV, Filimonov DA, Poroikov VV. ADVERPred-Web service for prediction of adverse effects of drugs. J Chem Inf Model 2018;58:8-11.
Yang H, Lou C, Sun L, Li J, Cai Y, Wang Z, et al.
admetSAR 2.0: Web-service for prediction and optimization of chemical ADMET properties. Bioinformatics 2019;35:1067-9.
Filimonov DA, Lagunin AA, Gloriozova TA, Rudik AV, Druzhilovskii DS, Pogodin PV, et al.
Prediction of the biological activity spectra of organic compounds using the PASS online web resource. Chem Heterocycl Compd 2014;50:444-57.
Banerjee P, Eckert AO, Schrey AK, Preissner R. ProTox-II: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Res 2018;46:W257-63.
Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017;7:42717.
de Azevedo JW, Fernandes TA, Fernandes JV, de Azevedo JC, Lanza DC, Bezerra CM, et al.
Biology and pathogenesis of human osteosarcoma. Oncol Lett 2020;19:1099-116.
Wu B, Yang W, Fu Z, Xie H, Guo Z, Liu D, et al.
Selected using bioinformatics and molecular docking analyses, PHA-793887 is effective against osteosarcoma. Aging (Albany NY) 2021;13:16425-44.
Zhang T, Li J, Yin F, Lin B, Wang Z, Xu J, et al.
Toosendanin demonstrates promising antitumor efficacy in osteosarcoma by targeting STAT3. Oncogene 2017;36:6627-39.
Xu X, Yu H, Xu Y. Ras ERK ½ signaling promotes the development of osteosarcoma by regulating H2BK12ac through CBP. Cancer Manag Res 2019;11:9153.
Zhang YL, Wang RC, Cheng K, Ring BZ, Su L. Roles of Rap1 signaling in tumor cell migration and invasion. Cancer Biol Med 2017;14:90-9.
Zhang J, Yu XH, Yan YG, Wang C, Wang WJ. PI3K/Akt signaling in osteosarcoma. Clin Chim Acta 2015;444:182-92.
Wang S, Zhong L, Li Y, Xiao D, Zhang R, Liao D, et al.
Up-regulation of PCOLCE by TWIST1 promotes metastasis in osteosarcoma. Theranostics 2019;9:4342-53.
Huang T, Zhou Y, Cao Y, Tao J, Zhou ZH, Hang DH. STK39, overexpressed in osteosarcoma, regulates osteosarcoma cell invasion and proliferation. Oncol Lett 2017;14:4599-604.
Wang L, Jin F, Qin A, Hao Y, Dong Y, Ge S, et al.
Targeting Notch1 signaling pathway positively affects the sensitivity of osteosarcoma to cisplatin by regulating the expression and/or activity of caspase family. Mol Cancer 2014;13:139.
Ren X, Cai J, Wang Y, Zhu X, Qian J, Han C, et al.
LncRNA ADAMTS9-AS2 in osteosarcoma inhibits cell proliferation and enhances paclitaxel sensitivity by suppressing microRNA-130a-5p. Eur J Inflamm 2020;18:1-11. [doi: 10.1177/2058739220934560].
Han J, Tian R, Yong B, Luo C, Tan P, Shen J, et al.
Gas6/Axl mediates tumor cell apoptosis, migration and invasion and predicts the clinical outcome of osteosarcoma patients. Biochem Biophys Res Commun 2013;435:493-500.
He A, Ma L, Huang Y, Zhang H, Duan W, Li Z, et al.
CDKL3 promotes osteosarcoma progression by activating Akt/PKB. Life Sci Alliance 2020;3:e202000648.
Seki K, Yoshikawa H, Shiiki K, Hamada Y, Akamatsu N, Tasaka K. Cisplatin (CDDP) specifically induces apoptosis via sequential activation of caspase-8, −3 and −6 in osteosarcoma. Cancer Chemother Pharmacol 2000;45:199-206.
Wen H, Wu Z, Hu H, Wu Y, Yang G, Lu J, et al.
The anti-tumor effect of pachymic acid on osteosarcoma cells by inducing PTEN and caspase 3/7-dependent apoptosis. J Nat Med 2018;72:57-63.
Liu P, Wang M, Li L, Jin T. Correlation between osteosarcoma and the expression of WWOX and p53. Oncol Lett 2017;14:4779-83.
Ong SM, Yamamoto H, Saeki K, Tanaka Y, Yoshitake R, Nishimura R, et al.
Anti-neoplastic effects of topoisomerase inhibitors in canine mammary carcinoma, melanoma, and osteosarcoma cell lines. Jpn J Vet Res 2017;65:17-28.
Taghipour YD, Hajialyani M, Naseri R, Hesari M, Mohammadi P, Stefanucci A, et al.
Nanoformulations of natural products for management of metabolic syndrome. Int J Nanomedicine 2019;14:5303-21.
Yao H, Liu J, Xu S, Zhu Z, Xu J. The structural modification of natural products for novel drug discovery. Expert Opin Drug Discov 2017;12:121-40.
Blakemore DC, Castro L, Churcher I, Rees DC, Thomas AW, Wilson DM, et al.
Organic synthesis provides opportunities to transform drug discovery. Nat Chem 2018;10:383-94.
Shah FH, Salman S, Idrees J, Idrees F, Shah ST, Khan AA, et al.
Current progress of phytomedicine in glioblastoma therapy. Curr Med Sci 2020;40:1067-74.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]