Bing Yang

Junfei Gu

Liang Feng

Ruyu Shi

Yanjun Yang

Frontiers in Pharmacology

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Editorial: Exploring thetherapeutic effects of synthetic,semi-synthetic and naturallyderived compounds againstcancerLiang Feng1*, Junfei Gu2, Yanjun Yang1, Bing Yang1 and Ruyu Shi11State Key Laboratory of Natural Medicines, Department of Traditional Chinese Pharmacy, ChinaPharmaceutical University, Nanjing, China, 2School of Chinese Medicine, School of Integrated Chineseand Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaKEYWORDSchemopreventive agent, natural medicine, anticancer, potential target discovery, actionmechanismsEditorial on the Research TopicExploring the therapeutic effects of synthetic, semi-synthetic and naturallyderived compounds against cancerThere are serious challenges in the treatment of cancer, which can sometimes be life-threatening. Indeed, natural compounds or naturally-derived compounds have beenrecommended in treating cancer because of their relative safety and low cost (Messehaet al., 2022). In recognition of this important and growing field of research, we hereby presenta Research Topic of primary research articles and reviews on the Research Topic of Focus oncompounds or compositions with potential activities including synthetic, semi-synthetic,structurally modified, natural sources, and Chinese medicines to explore their beneficialeffects on cancers and explore its potential mechanisms of action.Natural compounds are being recognized as promising candidates for anticancer therapydue to their safety and multitarget intrinsic features. In addition, numerous studies havefound that a natural compound may have multiple active targets rather than only one uniquetarget (Chen et al., 2021; Fakhri et al., 2021). Therefore, many natural products may playmultiple roles in cancer treatment. Plant extracts, in particular, have been for centuries usedas therapeutic agents (Lee et al., 2021), and are still object of extensive research for theirmanifold properties and mechanisms of action, that make them promising molecules fornovel cancer treatment strategies.This Research Topic brings together works that make significant contributions to theadvancement of research in the field of cancer therapy, taking into account the challengesinvolved in establishing effective treatments and the crucial role synthetic, semi-syntheticand naturally derived compounds plays in the development and progression of cancer.Zengshengping (ZSP) is a widely used antitumor traditional Chinese medicine compound inclinics. It is a Chinese herbal medicine formulation. Sun et al. used the Lewis lung cancer model,H&E staining, ELISA, immunohistochemistry and other techniques to investigate thedevelopment of lung cancer, tumor cell proliferation, immune organ index, inflammatoryfactor level to evaluate the efficacy of ZSP in the prevention and treatment of lung cancer.OPEN ACCESSEDITED AND REVIEWED BYOlivier Feron,Université catholique de Louvain,Belgium*CORRESPONDENCELiang Feng,wenmoxiushi@163.comRECEIVED 02 July 2023ACCEPTED 14 August 2023PUBLISHED 22 August 2023CITATIONFeng L, Gu J, Yang Y, Yang B and Shi R(2023), Editorial: Exploring thetherapeutic effects of synthetic, semi-synthetic and naturally derivedcompounds against cancer.Front. Pharmacol. 14:1251835.doi: 10.3389/fphar.2023.1251835COPYRIGHT©2023 Feng, Gu, Yang, Yang and Shi. Thisis an open-access article distributedunder the terms of the CreativeCommons Attribution License (CC BY).The use, distribution or reproduction inother forums is permitted, provided theoriginal author(s) and the copyrightowner(s) are credited and that the originalpublication in this journal is cited, inaccordance with accepted academicpractice. No use, distribution orreproduction is permitted which does notcomply with these terms.Frontiers in Pharmacology frontiersin.org01TYPE EditorialPUBLISHED 22 August 2023DOI 10.3389/fphar.2023.1251835Protein immunoblotting, immunohistochemistry and other methodswere used to investigate the physical barrier and immune barrier of theintestinal mucosa, 16Sr high-throughput sequencing technology wasused to investigate the intestinalmucosal biological barrier of Lewis lungcancer model mice and urethane-induced lung cancer model mice, andevaluate the effect of ZSP on intestinal mucosa of lung cancer mice.“Lung cancer”, “gut-lung axis”, and “treating the lung from theintestine” are three aspects of progressive development, and the roleof ZSP in the prevention and treatment of lung cancer is expounded.Chen et al. showed that the expression of PUMA (p53 upregulatedmodulator of apoptosis) was upregulated upon platycodin D treatment.Knockdown of PUMA resulted in attenuation of platycodin D-inducedapoptosis, indicating that PUMA upregulation is essential forplatycodin D to induce apoptosis. The induction of PUMAexpression by platycodin D treatment was through activation of AP-1 sincemutation of AP-1 binding site in the PUMApromoter abolishedthe PUMA promoter activity. Moreover, knockdown of JNK1, but notJNK2, significantly abolished the phosphorylation of c-Jun at Ser63 (acomponent of AP-1), decreased the platycodinD-induced expression ofPUMA and cleaved caspase 3, indicating that platycodin D inhibitsJNK1/AP-1 signaling pathway for apoptosis induction in suppression ofNSCLC (non-small cell lung cancer) growth, providing a newmechanism of how platycodin D suppresses NSCLC.Li et al. provided existing evidence and molecular mechanism ofTanshinone IIA’s anti-HCC effect but also reviews the liverprotectiveeffect of TsIIA and its impact on liver fibrosis, NAFLD, and other riskfactors for liver cancer. In addition, we also conducted networkpharmacological analysis on TsIIA and HCC to further screen andexplore the possible targets of TsIIA against hepatocellular carcinoma. Itis expected to provide a theoretical basis for the development of anti-HCC-related drugs based on TsIIA.Rita Volpe et al. studied the effect of hydroalcoholic extract fromdried leaves of Buxus sempervirens (BSHE) on four human cell lines(BMel melanoma cells, HCT116 colorectal carcinoma cells,PC3 prostate cancer cells, and HS27 skin fibroblasts) to ascertainits possible antineoplastic activity. BSHE appeared to promoteautophagic flow with its following blockade and consequentaccumulation of autophagosome or autolysosomes. Theantiproliferative effects of BSHE also involved cell cycleregulators such as p21 (HS27, BMel, and HCT116 cells) andcyclin B1 (HCT116, BMel, and PC3 cells) whereas, amongapoptosis markers, BSHE only decreased (30%–40% at 48 h) theexpression of the antiapoptotic protein survivin. It was concludedthat BSHE impairs autophagic flow with arrest of proliferation anddeath in both fibroblasts and cancer cells, being the latter muchmoresensitive to these effects.Xu et al. screened total of 90 genes for Dendrobin A anti-PDAC,and a PPI network for Dendrobin A anti-PDAC targets wasconstructed. Notably, a scale free module with 19 genes in the PPIindicated that the PPI is highly credible. Among these 19 genes, PLAUwas positively correlated with the cachexia status while negativelycorrelated with the overall survival of PDAC patients. Throughmolecular docking, Dendrobin A was found to bind to PLAU, andthe Dendrobin A treatment led to an attenuated PLAU expression inPDAC cells. Based on clinical tissue arrays, PLAU protein was highlyexpressed in PDAC cells compared to normal controls, and PLAUprotein levels were associated with the differentiation and lymph nodemetastatic status of PDAC. In vitro experiments further showed thatDendrobin A treatment significantly inhibited the proliferation,migration, and invasion, inducing apoptosis and arresting the cellcycle of PDAC cells at the G2/M phase.In the study by Chen et al. Cinobufacini injection (CI), an aqueousextract of Cutis Bufonis, is clinically used for cancer therapy in China,but its molecular mechanism for the treatment of osteosarcoma (OS)remains unclear. We constructed U2OS ectopic subcutaneous tumormodel to verify the anti-OS effect of CI in vivo. Meanwhile, cellproliferation of U2OS and MG63 cells was monitored in vitro usingthe CCK-8 assay, colony formation and morphological changes. Cellcycle arrest and apoptosis were detected by flow cytometry andWesternblot, which showed that CI significantly inhibited proliferation, inducedcell cycle arrest and apoptosis in human OS cells. The further RNA-seqresults identified that the Hippo signaling pathway was involved in theanti-OS effect of CI. YAP/TAZ are twomajor components of the Hippopathway in breast cancer and are positively regulated by prolylisomerase PIN1, we assessed their role in OS using bothclinicopathological sections and western blots. CI also inhibitedPIN1 enzyme activity in a dose-dependent manner, which resultedin impaired PIN1, YAP, and TAZ expression in vitro and in vivo.Additionally, 15 potential compounds of CI were found to occupy thePIN1 kinase domain and inhibit its activity. In summary, CI plays ananti-OS role by down-regulating the PIN1-YAP/TAZ pathway.Min et al. found that the atorvastatin use could increase the risk ofcolorectal cancer (odd ratio (OR) = 1.041, p = 0.035 by fixed-effectsinverse variance weighted (IVW) method (IVWFE), OR = 1.086, p = 0.005 by weighted median; OR = 1.101, p = 0.048 by weighted mode,respectively). According to the weighted median and weighted mode,atorvastatin could modestly decrease the risk of liver cell cancer (OR =0.989, p = 0.049, and OR = 0.984, p = 0.004, respectively) and head andneck cancer (OR = 0.972, p = 0.020). Besides, rosuvastatin use couldreduce the bile duct cancer risk by 5.2% via IVWEF method (OR = 0.948, p = 0.031). No significant causality was determined in simvastatinuse and pan-cancers via the IVWFE or multiplicative random-effectsIVW (IVWMRE) method if applicable (p > 0.05). There was nohorizontal pleiotropy observed in the MR analysis and the leave-one-out analysis proved the stability of the results.Zhang et al. identified EGFR from more than a dozen predictedtargets as a protein that directly binds to acacetin. Moreover,acacetin affected the level of phosphorylated EGFR. In vitro,acacetin promoted the apoptosis of GC cells. Importantly, EGFRagonists reversed the inhibitory effects of acacetin on the STAT3 andERK pathways. In vivo, acacetin decreased the protein levels ofpEGFR in tumors, resulting in increased GC xenograft tumorregression without obvious toxicity.In a case report study by Shen et al. they described a rare case ofidiopathic pulmonary fibrosis associated with the use of nab-paclitaxel and carboplatin in ovarian cancer. During treatment, itis necessary to maintain a high level of vigilance for patients withinterstitial pneumonia and engage the attention of clinicians toimprove medication safety. Early diagnosis and anti-fibrosis therapycan reverse lung damage.During the last few decades, an overwhelming number of bothpreclinical and clinical studies have demonstrated the potential ofsynthetic, semi-synthetic and naturally derived compounds in theprevention and treatment of cancer (Scott et al., 2013; Ren andKinghorn, 2019). Emerging evidence suggests that natural bioactivecompounds confer anticancer activities via impacting carcinogenFrontiers in Pharmacology frontiersin.org02Feng et al. 10.3389/fphar.2023.1251835metabolism, oxidative stress, inflammation, cell proliferation,apoptosis, autophagy, cell cycle regulation, epigenetic alteration,invasion, migration, adhesion, angiogenesis, and metastasis byregulating a plethora of cell signaling molecules, mediators andmodulators (Rios et al., 2009; Von and vollmar 2013; Deng et al.,2019; Xiao et al., 2022).In order to achieve the desired level of protection, it is imperativethat researchers take into account all relevantmechanisms and explore arange of comprehensive measures or drug combinations. Thedevelopment of molecular biology technology has led to the researchof targeted therapy using natural products or derivatives that are highlyselective for tumor as carriers, it is necessary to study the optimal dosefor protecting against different tumors, and chemically coupling thesefactors into biological treatments (Tobeiha et al., 2021). In addition,direct delivery of natural product to the tumor site can not only reducethe amount of natural product needed but also improve the efficacy andreduce adverse reactions. This opens up new ideas for the study ofprotective measures against cancer. On the one hand, there are stillexisting disparities between remarkably anticarcinogenic effects inpreclinical models and negative results in real-world observationalstudies. On the other hand, the potential confounding factors thatexisted in observational studies could also overlap the real influence ofstatin use in cancers (Zhi et al., 2020). Therefore, future well-designeddouble-blind randomized controlled trials are warranted to validate theexisting correlations we determined.Overall, the nine papers published on this Research Topichighlighted several natural products or traditional Chinesemedicine that can be characterized appropriately to enhanceimmunotherapy of diverse human cancers. In summary, naturalproducts with well-characterized structures or traditional Chinesemedicines with well-defined functions have great potential in thetreatment of cancer. They can be used in combination with otherimmunotherapies as chemoprevention, chemotherapy or adjuvanttherapy to manage various cancers. However, in-depth studies withmore physiologically and pathologically relevant models are neededto determine its efficacy and clinical effectiveness. Therefore, furtherverification of the efficacy of these natural bioactive substances andtraditional Chinese medicines will provide more convincingevidence for future cancer treatment or adjuvant therapy.Author contributionsAll authors listed havemade a substantial, direct, and intellectualcontribution to the work and approved it for publication.AcknowledgmentsThis Research Topic would not have been possible without thecontribution of all the researchers and authors. As Guest-Editors, wewould like to thank all the authors for their substantial contributiontoward the success of this Research Topic. We would like to thankthe reviewers for their time and valuable constructive comments andsuggestions. Lastly, a special word of appreciation to the members ofthe Frontiers Editorial Office, for their assistance in making thiswork a success.Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.ReferencesChen, H., Gao, Y., Wu, J., Chen, Y., Chen, B., Hu, J., et al. (2021). Exploringtherapeutic potentials of baicalin and its aglycone baicalein for hematologicalmalignancies. Cancer. Lett. 354 (1), 5–11. doi:10.1016/j.canlet.2014.08.003Deng, S., Shanmugam, M. K., Kumar, A. P., Yap, C. T., Sethi, G., and Bishayee, A.(2019). Targeting autophagy using natural compounds for cancer prevention andtherapy: autophagy, cancer, and natural compounds. Cancer 125 (8), 1228–1246.doi:10.1002/cncr.31978Fakhri, S., Moradi, S., Ash-Rafzadeh, A., and Bishayee, A. (2021). Targeting cellularsenescence in cancer by plant secondary metabolites: A systematic review. Pharmacol.Res. 177, 105961. doi:10.1016/j.phrs.2021.105961Lee, R. T., Kwon, N., Wu, J., To, C., To, S., Szmulewitz, R., et al. (2021). Prevalence ofpotential interactions of medications, including herbs and supplements, before, during,and after chemotherapy in patients with breast and prostate cancer. Cancer 127 (11),1827–1835. doi:10.1002/cncr.33324Messeha, S. S., Zarmouh, N. O., Antonie, L., and Soliman, K. F. A. (2022).Sanguinarine inhibition of TNF-α-Induced CCL2, IKBKE/NF-κB/ERK1/2 signalingpathway, and cell migration in human triple-negative breast cancer cells. Int. J. Mol. Sci.23 (15), 8329. doi:10.3390/ijms23158329Ren, Y., and Kinghorn, A. D. (2019). Natural product triterpenoids and their semi-synthetic derivatives with potential anticancer activity. Planta. Med. 85 (11-12),802–814. doi:10.1055/a-0832-2383Ríos, J. L., Recio, M. C., Escandell, J. M., and Andújar, I. (2009). Inhibition oftranscription factors by plant-derived compounds and their implications ininflammation and cancer. Curr. Pharm. Des. 15 (11), 1212–1237. doi:10.2174/138161209787846874Scott, D., Chen, J. M., Bae, Y., and Rohr, J. (2013). Semi-synthetic mithramycin SAderivatives with improved anticancer activity. Chem. Biol. Drug. Des. 81 (5), 615–624.doi:10.1111/cbdd.12107Tobeiha, M., Rajabi, A., Raisi, A., Mohajeri, M., Yazdi, S. M., Davoodvandi, A., et al.(2021). Potential of natural products in osteosarcoma treatment: focus on molecularmechanisms. Biomed. Pharmacother. 144, 112257. doi:10.1016/j.biopha.2021.112257Von, S. K., and Vollmar, A. M. (2013). Targeting apoptosis pathways by naturalcompounds in cancer: marine compounds as lead structures and chemical tools forcancer therapy. Cancer. Lett. 332 (2), 295–303. doi:10.1016/j.canlet.2010.07.004Xiao,Q., Deng, B., Akbari, A., Liu,Q., andZhu, B. (2022). The ketogenic diet could improvethe efficacy of curcumin and Oldenlandia diffusa extract in the treatment of gastric cancer byincreasing miR340 expression and apoptosis mediated by autophagy, oxidative stress, andangiogenesis. J. Food. Biochem. 46 (12), e14407. doi:10.1111/jfbc.14407Zhi, K., Wang, J., Zhao, H., and Yang, X. (2020). Self-assembled small moleculenatural product gel for drug delivery: A breakthrough in new application of smallmolecule natural products. Acta. Pharm. Sin. B 10 (5), 913–927. doi:10.1016/j.apsb.2019.09.009Frontiers in Pharmacology frontiersin.org03Feng et al. 10.3389/fphar.2023.1251835

Editorial: Exploring the therapeutic effects of synthetic, semi-synthetic and naturally derived compounds against cancer

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Editorial: Exploring the therapeutic effects of synthetic, semi-synthetic and naturally derived compounds against cancer

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