Precision cancer medicine is a tailored treatment approach for individual cancer patients with different genomic characteristics. Mutated or hyperactive oncogenes have served as main drug targets in current precision cancer medicine, while defective or inactivated tumor suppressors in general have not been considered as druggable targets. Synthetic lethality is one of very few approaches that enable to target defective tumor suppressors with pharmacological agents. Synthetic lethality exploits cancer cell dependency on a protein or pathway, which arises when the function of a tumor suppressor is defective. This approach has been proven to be effective in clinical settings since the successful clinical introduction of BRCA-PARP synthetic lethality for the treatment of breast and ovarian cancer with defective BRCA. Subsequently, large-scale screenings with RNAi, CRISPR/Cas9-sgRNAs, and chemical libraries have been applied to identify synthetic lethal partners of tumor suppressors. Natural products are an important source for the discovery of pharmacologically active small molecules. However, little effort has been made in the discovery of synthetic lethal small molecules from natural products. This review introduces recent advances in the discovery of natural products targeting cancer cell dependency and discusses potentials of natural products in the precision cancer medicine.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Chandrashekar P, et al. Somatic selection distinguishes oncogenes and tumor suppressor genes. Bioinformatics 2020;36:1712–17.
Lee EY, Muller WJ. Oncogenes and tumor suppressor genes. Cold Spring Harb Perspect Biol 2010;2:a003236.
Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 2015;161:205–14.
Pinker K, Chin J, Melsaether AN, Morris EA, Moy L. Precision medicine and radiogenomics in breast cancer: new approaches toward diagnosis and treatment. Radiology 2018;287:732–47.
Jackson SE, Chester JD. Personalised cancer medicine. Int J Cancer 2015;137:262–6.
Bonelli P, Borrelli A, Tuccillo FM, Silvestro L, Palaia R, Buonaguro FM. Precision medicine in gastric cancer. World J Gastrointest Oncol 2019;11:804–29.
Hochhaus A, et al. Long-term outcomes of Imatinib treatment for chronic myeloid leukemia. N. Engl J Med 2017;376:917–27.
Moja L, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012:CD006243.
Chapman PB, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–16.
Lucchesi JC. Synthetic lethality and semi-lethality among functionally related mutants of Drosophila melanfgaster. Genetics 1968;59:37–44.
Dobzhansky T. Genetics of natural populations; recombination and variability in populations of Drosophila pseudoobscura. Genetics 1946;31:269–90.
O’Neil NJ, Bailey ML, Hieter P. Synthetic lethality and cancer. Nat Rev Genet 2017;18:613–23.
Hartwell LH, Szankasi P, Roberts CJ, Murray AW, Friend SH. Integrating genetic approaches into the discovery of anticancer drugs. Science 1997;278:1064–8.
Lord CJ, Tutt AN, Ashworth A. Synthetic lethality and cancer therapy: lessons learned from the development of PARP inhibitors. Annu Rev Med 2015;66:455–70.
Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science 2017;355:1152–58.
Fong PC, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009;361:123–34.
Farmer H, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917–21.
Bryant HE, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005;434:913–7.
Echeverri CJ, Perrimon N. High-throughput RNAi screening in cultured cells: a user’s guide. Nat Rev Genet 2006;7:373–84.
Iorns E, Lord CJ, Turner N, Ashworth A. Utilizing RNA interference to enhance cancer drug discovery. Nat Rev Drug Discov 2007;6:556–68.
McDonald ER, et al. Project DRIVE: a compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi screening. Cell 2017;170:577–92 e10.
Behan FM, et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 2019;568:511–16.
Beetham H, et al. A high-throughput screen to identify novel synthetic lethal compounds for the treatment of E-cadherin-deficient cells. Sci Rep. 2019;9:12511.
Shi C, Yang EJ, Liu Y, Mou PK, Ren G, Shim JS. Bromodomain and extra-terminal motif (BET) inhibition is synthetic lethal with loss of SMAD4 in colorectal cancer cells via restoring the loss of MYC repression. Oncogene 2021;40:937–50.
Wang J, et al. FDA-approved drug screen identifies proteasome as a synthetic lethal target in MYC-driven neuroblastoma. Oncogene 2019;38:6737–51.
Rodrigues T, Reker D, Schneider P, Schneider G. Counting on natural products for drug design. Nat Chem 2016;8:531–41.
Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 2020;83:770–803.
Martinez-Outschoorn UE, Peiris-Pages M, Pestell RG, Sotgia F, Lisanti MP. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 2017;14:11–31.
Liberti MV, Locasale JW. The Warburg Effect: how does it benefit cancer cells? Trends Biochem Sci 2016;41:211–18.
Mohanti BK, et al. Improving cancer radiotherapy with 2-deoxy-D-glucose: phase I/II clinical trials on human cerebral gliomas. Int J Radiat Oncol Biol Phys 1996;35:103–11.
Raez LE, et al. A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 2013;71:523–30.
Stein M, et al. Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies. Prostate 2010;70:1388–94.
El Sayed SM, et al. Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study. Chin J Cancer 2014;33:356–64.
Chapiro J, et al. Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer. 2014;20:6406-17.
McDonald PC, et al. A phase 1 study of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors. 2020;43:484-90.
Ying H, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 2012;149:656–70.
He TL, Zhang YJ, Jiang H, Li XH, Zhu H, Zheng KL. The c-Myc-LDHA axis positively regulates aerobic glycolysis and promotes tumor progression in pancreatic cancer. Med Oncol 2015;32:187.
Li Z, Liu J, Que L, Tang X. The immunoregulatory protein B7-H3 promotes aerobic glycolysis in oral squamous carcinoma via PI3K/Akt/mTOR pathway. 2019;10:5770-84.
Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest 2013;123:3664–71.
Nicolaou KC, Kang Q, Ng SY, Chen DY. Total synthesis of englerin A. J Am Chem Soc 2010;132:8219–22.
Ratnayake R, Covell D, Ransom TT, Gustafson KR, Beutler JA, Englerin A. a selective inhibitor of renal cancer cell growth, from Phyllanthus engleri. Org Lett 2009;11:57–60.
Gossage L, Eisen T, Maher ERVHL. the story of a tumour suppressor gene. Nat Rev Cancer 2015;15:55–64.
Keith B, Johnson RS, Simon MC. HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 2011;12:9–22.
Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr., Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci USA 1996;93:10595–9.
Sourbier C, et al. Englerin A stimulates PKCtheta to inhibit insulin signaling and to simultaneously activate HSF1: pharmacologically induced synthetic lethality. Cancer Cell 2013;23:228–37.
Li Y, et al. Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). J Biol Chem 2004;279:45304–7.
Griffin ME, et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999;48:1270–4.
Dai C, Whitesell L, Rogers AB, Lindquist S. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 2007;130:1005–18.
Williams RT, Yu AL, Diccianni MB, Theodorakis EA, Batova A. Renal cancer-selective Englerin A induces multiple mechanisms of cell death and autophagy. J Exp Clin Cancer Res 2013;32:57.
Akbulut Y, et al. (-)-Englerin A is a potent and selective activator of TRPC4 and TRPC5 calcium channels. Angew Chem Int Ed Engl 2015;54:3787–91.
Carson C, et al. Englerin A agonizes the TRPC4/C5 cation channels to inhibit tumor cell line proliferation. PLoS ONE 2015;10:e0127498.
Rodrigues T, et al. Unveiling (-)-Englerin A as a modulator of L-type calcium channels. Angew Chem Int Ed Engl 2016;55:11077–81.
Batova A, et al. Englerin A induces an acute inflammatory response and reveals lipid metabolism and ER stress as targetable vulnerabilities in renal cell carcinoma. PLoS ONE 2017;12:e0172632.
Wu Z, Zhao S, Fash DM, Li Z, Chain WJ, Beutler JA. Englerins: a comprehensive review. J Nat Prod 2017;80:771–81.
Fash DM, et al. Synthesis of a stable and orally bioavailable englerin analogue. Bioorg Med Chem Lett 2016;26:2641–4.
Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008;8:387–98.
Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene 2017;36:1461–73.
Zang ZJ, et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet 2012;44:570–4.
Schulze K, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 2015;47:505–11.
Cancer Genome Atlas Research N, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497:67–73.
Yu B, Huang Z, Zhang M, Dillard DR, Ji H. Rational design of small-molecule inhibitors for beta-catenin/T-cell factor protein-protein interactions by bioisostere replacement. ACS Chem Biol 2013;8:524–9.
Gail R, Frank R, Wittinghofer A. Systematic peptide array-based delineation of the differential beta-catenin interaction with Tcf4, E-cadherin, and adenomatous polyposis coli. J Biol Chem 2005;280:7107–17.
Hsieh TH, et al. A novel cell-penetrating peptide suppresses breast tumorigenesis by inhibiting beta-catenin/LEF-1 signaling. Sci Rep. 2016;6:19156.
Grossmann TN, Yeh JT, Bowman BR, Chu Q, Moellering RE, Verdine GL. Inhibition of oncogenic Wnt signaling through direct targeting of beta-catenin. Proc Natl Acad Sci USA 2012;109:17942–7.
Shin SH, et al. A small molecule inhibitor of the beta-catenin-TCF4 interaction suppresses colorectal cancer growth In vitro and In vivo. EBioMedicine 2017;25:22–31.
Esposito MT, et al. Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors. Nat Med 2015;21:1481–90.
Delmore JE, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011;146:904–17.
Shikata Y, et al. Mitochondrial uncoupler exerts a synthetic lethal effect against beta-catenin mutant tumor cells. Cancer Sci 2017;108:772–84.
Yu WK, et al. Targeting beta-catenin signaling by natural products for cancer prevention and therapy. Front Pharmacol 2020;11:984.
Woo AJ, Strohl WR, Priestley ND. Nonactin biosynthesis: the product of nonS catalyzes the formation of the furan ring of nonactic acid. Antimicrob Agents Chemother 1999;43:1662–8.
Nelson ME, Priestley ND. Nonactin biosynthesis: the initial committed step is the condensation of acetate (malonate) and succinate. J Am Chem Soc 2002;124:2894–902.
Wu Y, Sun YP. Synthesis of nonactin and the proposed structure of trilactone. Org Lett 2006;8:2831–4.
Kusche BR, Phillips JB, Priestley ND. Nonactin biosynthesis: setting limits on what can be achieved with precursor-directed biosynthesis. Bioorg Med Chem Lett 2009;19:1233–5.
Kusche BR, Smith AE, McGuirl MA, Priestley ND. Alternating pattern of stereochemistry in the nonactin macrocycle is required for antibacterial activity and efficient ion binding. J Am Chem Soc 2009;131:17155–65.
Kaushik V, Yakisich JS, Kumar A, Azad N, Iyer AKV. Ionophores: potential use as anticancer drugs and chemosensitizers. Cancers. 2018;10:360.
Pate KT, et al. Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer. EMBO J 2014;33:1454–73.
Fang Y, et al. CD36 inhibits beta-catenin/c-myc-mediated glycolysis through ubiquitination of GPC4 to repress colorectal tumorigenesis. Nat Commun 2019;10:3981.
Vallee A, Lecarpentier Y, Guillevin R, Vallee JN. Aerobic glycolysis hypothesis through WNT/beta-catenin pathway in exudative age-related macular degeneration. J Mol Neurosci 2017;62:368–79.
Pampaloni F, et al. A novel cellular spheroid-based autophagy screen applying live fluorescence microscopy identifies nonactin as a strong inducer of autophagosomal turnover. SLAS Discov 2017;22:558–70.
Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer 2016;16:110–20.
Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci 2004;95:866–71.
Audeh MW, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 2010;376:245–51.
Feng Z, et al. Rad52 inactivation is synthetically lethal with BRCA2 deficiency. Proc Natl Acad Sci USA 2011;108:686–91.
Chen CC, et al. ATM loss leads to synthetic lethality in BRCA1 BRCT mutant mice associated with exacerbated defects in homology-directed repair. Proc Natl Acad Sci USA 2017;114:7665–70.
Albarakati N, et al. Targeting BRCA1-BER deficient breast cancer by ATM or DNA-PKcs blockade either alone or in combination with cisplatin for personalized therapy. Mol Oncol 2015;9:204–17.
Zhang B, et al. BRCA1 deficiency sensitizes breast cancer cells to bromodomain and extra-terminal domain (BET) inhibition. Oncogene 2018;37:6341–56.
Zhang B, et al. Class I histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells. Acta Pharm Sin B 2020;10:615–27.
Carbajosa S, et al. Polo-like kinase 1 inhibition as a therapeutic approach to selectively target BRCA1-deficient cancer cells by synthetic lethality induction. Clin Cancer Res 2019;25:4049–62.
Killock D. Targeted therapies: DNA polymerase theta-a new target for synthetic lethality? Nat Rev Clin Oncol 2015;12:125.
Srinivasan G, et al. MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers. Proc Natl Acad Sci USA 2019;116:17438–43.
García IA, et al. Synthetic lethal activity of benzophenanthridine alkaloids from zanthoxylum coco against BRCA1-deficient cancer cells. Front Pharmacol 2020;11:593845.
Hu J, et al. Benzophenanthridine alkaloids from Zanthoxylum nitidum (Roxb.) DC, and their analgesic and anti-inflammatory activities. Chem Biodivers 2006;3:990–5.
Cai M, Zhou Y, Wang X, Li R, Liao X, Ding L. Rapid structural characterization of isomeric benzo[c]phenanthridine alkaloids from the roots of Zanthoxylum nitidium by liquid chromatography combined with electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 2007;21:1931–6.
Gakunju DM, et al. Potent antimalarial activity of the alkaloid nitidine, isolated from a Kenyan herbal remedy. Antimicrob Agents Chemother 1995;39:2606–9.
Bouquet J, Rivaud M, Chevalley S, Deharo E, Jullian V, Valentin A. Biological activities of nitidine, a potential anti-malarial lead compound. Malar J 2012;11:67.
Khan H, Hadda TB, Touzani R. Diverse therapeutic potential of nitidine, a comprehensive review. Curr Drug Metab 2018;19:986–91.
Yang N, et al. Nitidine chloride exerts anti-inflammatory action by targeting Topoisomerase I and enhancing IL-10 production. Pharmacol Res 2019;148:104368.
Del Poeta M, et al. Comparison of in vitro activities of camptothecin and nitidine derivatives against fungal and cancer cells. Antimicrob Agents Chemother 1999;43:2862–8.
Sun M, et al. Hedgehog pathway is involved in nitidine chloride induced inhibition of epithelial-mesenchymal transition and cancer stem cells-like properties in breast cancer cells. Cell Biosci 2016;6:44.
Xiong DD, et al. High throughput circRNA sequencing analysis reveals novel insights into the mechanism of nitidine chloride against hepatocellular carcinoma. Cell Death Dis 2019;10:658.
Mou H, et al. Nitidine chloride inhibited the expression of S phase kinase-associated protein 2 in ovarian cancer cells. Cell Cycle 2017;16:1366–75.
Fang Z, et al. Nitidine chloride inhibits renal cancer cell metastasis via suppressing AKT signaling pathway. Food Chem Toxicol 2013;60:246–51.
Zhai H, et al. Nitidine chloride inhibits proliferation and induces apoptosis in colorectal cancer cells by suppressing the ERK signaling pathway. Mol Med Rep. 2016;13:2536–42.
Chen J, et al. Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer. Mol Cancer Ther 2012;11:277–87.
Yang IH, et al. Nitidine chloride represses Mcl-1 protein via lysosomal degradation in oral squamous cell carcinoma. J Oral Pathol Med 2018;47:823–29.
Liu M, et al. Nitidine chloride inhibits the malignant behavior of human glioblastoma cells by targeting the PI3K/AKT/mTOR signaling pathway. Oncol Rep. 2016;36:2160–8.
Xu H, et al. Nitidine chloride inhibits SIN1 expression in osteosarcoma cells. Mol Ther Oncolytics 2019;12:224–34.
Li P, et al. Cell cycle arrest and apoptosis induction activity of nitidine chloride on acute myeloid leukemia cells. Med Chem 2018;14:60–66.
Liu N, et al. Novel agent nitidine chloride induces erythroid differentiation and apoptosis in CML cells through c-Myc-miRNAs axis. PLoS ONE 2015;10:e0116880.
Kang M, Ou H, Wang R, Liu W, Tang A. The effect of nitidine chloride on the proliferation and apoptosis of nasopharyngeal carcinoma cells. J BUON 2014;19:130–6.
Shi Y, Cao T, Sun Y, Xia J, Wang P, Ma J. Nitidine Chloride inhibits cell proliferation and invasion via downregulation of YAP expression in prostate cancer cells. Am J Transl Res 2019;11:709–20.
Cui Y, et al. Antitumor functions and mechanisms of nitidine chloride in human cancers. J Cancer 2020;11:1250–56.
Baek HJ, et al. Inhibition of AKT suppresses the initiation and progression of BRCA1-associated mammary tumors. Int J Biol Sci 2018;14:1769–81.
Villafañez F, et al. AKT inhibition impairs PCNA ubiquitylation and triggers synthetic lethality in homologous recombination-deficient cells submitted to replication stress. Oncogene 2019;38:4310–24.
Coussy F, et al. BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers. Sci Transl Med 2020;12:12.
Li L, et al. The contribution of human OCT1, OCT3, and CYP3A4 to nitidine chloride-induced hepatocellular toxicity. Drug Metab Dispos 2014;42:1227–34.
Li LP, et al. Role of OCT2 and MATE1 in renal disposition and toxicity of nitidine chloride. Br J Pharmacol 2016;173:2543–54.
Wilson BAP. Creating and screening natural product libraries. Nat Prod Rep. 2020;37:893–918.
This study was supported by the Science and Technology Development Fund, Macau SAR (FDCT/0107/2020/A1 and FDCT/0030/2020/A to J.S.S.) and Multi-Year Research Grant, University of Macau (MYRG2019-00116-FHS and MYRG2020-00229-FHS to J.S.S).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Shi, C., Yang, E.J., Tao, S. et al. Natural products targeting cancer cell dependency. J Antibiot 74, 677–686 (2021). https://doi.org/10.1038/s41429-021-00438-x