Cyanobacteria are rich in bioactive compounds that exhibit diverse biological activities, including antiproliferative, cytotoxic, and antineoplastic properties. Many of these compounds are currently being studied in clinical trials. In this paper, newly discovered bioactive compounds from various cyanobacteria species that have demonstrated anticancer effects against multiple cancer cell lines, such as apratoxin, symplostatin 1, bartolosides, caylobolide, bisebromoamides, carmaphycins, and anaenamides, are reviewed. At present, there are no clear guidelines on approving cyanobacteria-derived bioactive compounds for use in treating diseases. While it is not uncommon that the intake of these compounds is accompanied by side effects, investigations on these compounds should focus on increasing the safety and efficacy of the compounds, or at least tread a fine line between drug safety and effectiveness for cancer patients. This review overviews the efficacy and cytotoxicity of cyanobacteria-derived bioactive compounds, providing researchers insights into how to maximize the benefits of these compounds through research.

1. IARC, 2021, Global Cancer Observatory. France: International Agency for Research on Cancer.

2. Hussein HA, Abdullah MA, 2020, Anticancer compounds derived from marine diatoms. Mar Drugs, 18: 356. https://doi.org/10.3390/md18070356

3. Hussein HA, Khaphi FL, 2023, The apoptotic activity of curcumin against oral cancer cells without affecting normal cells in comparison to paclitaxel activity. Appl Biochem Biotechnol, 195: 5019–5033. https://doi.org/10.1007/s12010-023-04454-5

4. Salem O, El Assi R, Saleh M, 2020, Bioactive constituents of three algal species extracts and their anticancer activity against human cancer cell lines. Egypt J Phycol, 21: 1–18.

5. Kar J, Ramrao DP, Zomuansangi R, et al., 2022, Revisiting the role of cyanobacteria-derived metabolites as antimicrobial agent: A 21st century perspective. Front Microbiol, 13: 103441. https://doi.org/10.3389/fmicb.2022.1034471

6. Nainangu P, Antonyraj APM, Subramanian K, et al., 2020, In vitro screening of antimicrobial, antioxidant, cytotoxic activities, and characterization of bioactive substances from freshwater Cyanobacteria Oscillatoria sp. SSCM01 and Phormidium sp. SSCM02. Biocatal Agric Biotechnol, 29: 101772.

7. Khalifa SAM, Shedid ES, Saied EM, et al., 2021, Cyanobacteria--from the oceans to the potential biotechnological and biomedical applications. Mar Drugs, 19: 241. https://doi.org/10.3390/md19050241

8. Costa M, Garcia M, Costa-Rodrigues J, et al., 2014, Exploring bioactive properties of marine cyanobacteria isolated from the Portuguese coast: High potential as a source of anticancer compounds. Mar Drugs, 12: 98–114. https://doi.org/10.3390/md12010098

9. Qamar H, Hussain K, Soni A, et al., 2021, Cyanobacteria as natural therapeutics and pharmaceutical potential: Role in antitumor activity and as nanovectors. Molecules, 26: 247. https://doi.org/10.3390/molecules26010247

10. Mehta A, Soni VK, Shukla D, et al., 2020, Cyanobacteria: A potential source of anticancer drugs. In: Advances in Cyanobacterial Biology. United States: Academic Press, p369–384. https://doi.org/10.1016/B978-0-12-819311-2.00024-3

11. Jones MR, Pinto E, Torres MA, et al., 2021, CyanoMetDB, a comprehensive public database of secondary metabolites from Cyanobacteria. Water Res, 196: 117017. https://doi.org/10.1016/j.watres.2021.117017

12. Zahra Z, Choo DH, Lee H, et al., 2020, Cyanobacteria: Review of current potentials and applications. Environments, 7: 13.

13. Pooja S, Niveshika, 2022, Insight into the potential cyanobacterial metabolites and their screening strategies. Biosci Biotechnol Res Asia, 19: 255–279.

14. Pattnaik S, Singh L, 2020, Cyanobacteria bioactive compound, their production and extraction with pharmaceutical applications - a review. Int J Curr Microbiol Appl Sci, 9: 3394–3405.

15. Sosa-Hernández JE, Escobedo-Avellaneda Z, Iqbal HMN, et al., 2018, State-of-the-art extraction methodologies for bioactive compounds from algal biome to meet bio-economy challenges and opportunities. Molecules, 23: 2953. https://doi.org/10.3390/molecules23112953

16. Kumar R, Tewari AK, 2018, Medicinal properties of marine plants. In: Synthesis of Medicinal Agents from Plants. Netherlands: Elsevier Ltd., p257–282. https://doi.org/10.1016/B978-0-08-102071-5.00011-8

17. Luesch H, Yoshida WY, Moore RE, et al., 2001, Total structure determination of apratoxin A, a potent novel cytotoxin from the marine cyanobacterium Lyngbya majuscula. J Am Chem Soc, 123: 5418–5423. https://doi.org/10.1021/ja010453j

18. Cai W, Chen QY, Dang LH, et al., 2017, Apratoxin S10, a dual inhibitor of angiogenesis and cancer cell growth to treat highly vascularized tumors. ACS Med Chem Lett, 8: 1007–1012. https://doi.org/10.1021/acsmedchemlett.7b00192

19. Tan LT, 2012, Marine Cyanobacteria: A treasure trove of bioactive secondary metabolites for drug discovery. In: Studies in Natural Products Chemistry. Vol. 36. Netherlands: Elsevier, p67–110.

20. Gutiérrez M, Suyama TL, Engene N, et al., 2008, Apratoxin D, a potent cytotoxic cyclodepsipeptide from papua new Guinea collections of the marine Cyanobacteria Lyngbya majuscula and Lyngbya sordida. J Nat Prod, 71: 1099–1103. https://doi.org/10.1021/np800121a

21. Tarsis EM, Rastelli EJ, Wengryniuk SE, et al., 2015, The apratoxin marine natural products: Isolation, structure determination, and asymmetric total synthesis. Tetrahedron, 71: 5029–5044.

22. Matthew S, Schupp PJ, Luesch H, 2008, Apratoxin E, a cytotoxic peptolide from a guamanian collection of the marine cyanobacterium Lyngbya bouillonii. J Nat Prod, 71: 1113–1116. https://doi.org/10.1021/np700717s

23. Thornburg CC, Cowley ES, Sikorska J, et al., 2013, Apratoxin H and Apratoxin A sulfoxide from the red sea cyanobacterium Moorea producens. J Nat Prod, 76: 1781−1788. https://doi.org/10.1021/np4004992

24. Cai1 W, Ratnayake R, Gerber MH, et al., 2019, Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived xenograft (PDX) model. Invest New Drugs, 37: 364–374. https://doi.org/10.1007/s10637-018-0647-0

25. Gunasekera SP, Owle CS, Montaser R, et al., 2011, Malyngamide 3 and cocosamides A and B from the marine cyanobacterium Lyngbya majuscula from Cocos Lagoon, guam. J Nat Prod, 74: 871–876. https://doi.org/10.1021/np1008015

26. Michon S, Cavelier F, Salom-Roig XJ, 2021, Synthesis and biological activities of cyclodepsipeptides of aurilide family from marine origin. Mar Drugs, 19: 55. https://doi.org/10.3390/md19020055

27. Han B, Gross H, Goeger DE, et al., 2006, Aurilides B and C, cancer cell toxins from a Papua new Guinea collection of the marine cyanobacterium Lyngbya majuscula. J Nat Prod, 69: 572–575. https://doi.org/10.1021/np0503911

28. Robles-Bañuelos B, Durán-Riveroll LM, Rangel-López E, et al., 2022, Marine Cyanobacteria as sources of lead anticancer compounds: A review of families of metabolites with cytotoxic, antiproliferative, and antineoplastic effects. Molecules, 27: 4814. https://doi.org/10.3390/molecules27154814

29. Yao G, Wang W, Ao L, et al., 2018, Improved total synthesis and biological evaluation of coibamide A analogues. J Med Chem, 61: 8808–8916. https://doi.org/10.1021/acs.jmedchem.8b01141

30. Medina RA, Goeger DE, Hills P, et al., 2008, Coibamide A, a potent antiproliferative cyclic depsipeptide from the panamanian marine cyanobacterium Leptolyngbya sp. J Am Chem Soc, 130: 6324–6325. https://doi.org/10.1021/ja801383f

31. Kazemi S, Kawaguchi S, Badr CE, et al., 2021, Targeting of HER/ErbB family proteins using broad spectrum Sec61 inhibitors coibamide A and apratoxin A. Biochem Pharmacol, 183: 114317. https://doi.org/10.1016/j.bcp.2020.114317

32. Shi W, Lu D, Wu C, et al., 2021, Coibamide A kills cancer cells through inhibiting autophagy. Biochem Biophys Res Commun, 547: 52–58. https://doi.org/10.1016/j.bbrc.2021.01.112

33. Tranter D, Paatero AO, Kawaguchi S, et al., 2020, Coibamide A targets Sec61 to prevent biogenesis of secretory and membrane proteins. ACS Chem Biol, 15: 2125–2136. https://doi.org/10.1021/acschembio.0c00325

34. Serrill JD, Wan X, Hau AM, et al., 2016, Coibamide A, a natural lariat depsipeptide, inhibits VEGFA/VEGFR2 expression and suppresses tumor growth in glioblastoma xenografts. Invest New Drugs, 34: 24–40. https://doi.org/10.1007/s10637-015-0303-x

35. Mooberry SL, Leal RM, Tinley TL, et al., 2003, The molecular pharmacology of symplostatin 1: A new antimitotic dolastatin 10 analog. Int J Cancer, 104: 512–521. https://doi.org/10.1002/ijc.10982

36. MacMillan JB, Molinski TF, 2002, Caylobolide A, a unique 36-membered macrolactone from a bahamian Lyngbya majuscula. Org Lett, 4: 1535–1538. https://doi.org/10.1021/ol025759p

37. Salvador LA, Paul VJ, Luesch H, 2010, Caylobolide B, a macrolactone from symplostatin 1-producing marine Cyanobacteria Phormidium spp. from Florida. J Nat Prod, 73: 1606–1609. https://doi.org/10.1021/np100467d

38. Tao Y, Li P, Zhang D, et al., 2018, Samholides, swinholide-related metabolites from a marine Cyanobacterium cf. Phormidium sp. J Org Chem, 83: 3034–3046. https://doi.org/10.1021/acs.joc.8b00028

39. Afonso TB, Costa MS, Rezende De Castro R, et al., 2016, Bartolosides E-K from a marine coccoid cyanobacterium. J Nat Prod, 79: 2504–2513. https://doi.org/10.1021/acs.jnatprod.6b00351

40. Sasaki H, Teruya T, Fukazawa H, et al., 2011, Revised structure and structure-activity relationship of bisebromoamide and structure of norbisebromoamide from the marine cyanobacterium Lyngbya sp. Tetrahedron, 67: 990–994.

41. Suzuki K, Mizuno R, Suenaga K, et al., 2013, Bisebromoamide, an extract from Lyngbya species, induces apoptosis through ERK and mTOR inhibitions in renal cancer cells. Cancer Med, 2: 32–39. https://doi.org/10.1002/cam4.53

42. Johnston HJ, Boys SK, Makda A, et al., 2016, Naturally inspired peptide leads: Alanine scanning reveals an actin-targeting thiazole analogue of bisebromoamide. Chembiochem, 17: 1621–1627. https://doi.org/10.1002/cbic.201600257

43. Pereira AR, Kale AJ, Fenley AT, et al., 2012, The carmaphycins, new proteasome inhibitors exhibiting an α,β-epoxyketone warhead from a marine cyanobacterium. Chembiochem, 13: 810–817. https://doi.org/10.1002/cbic.201200007

44. Brumley DA, Gunasekera SP, Chen QY, et al., 2020, Discovery, total synthesis and SAR of anaenamides A and B: Anticancer cyanobacterial depsipeptides with a chlorinated pharmacophore. Org Lett, 22: 4235–4239. https://doi.org/10.1021/acs.orglett.0c01281

45. Trauner D, Shemet A, 2020, Discovery and total synthesis of anaenamides A and B. Synfacts, 16: 0982.

46. Quintana J, Bayona LM, Castellanos L, et al., 2014, Almiramide D, cytotoxic peptide from the marine cyanobacterium Oscillatoria nigroviridis. Bioorg Med Chem, 22: 6789–6795. https://doi.org/10.1016/j.bmc.2014.10.039

47. Yu HB, Glukhov E, Li Y, et al., 2019, Cytotoxic microcolin lipopeptides from the marine cyanobacterium Moorea producens. J Nat Prod, 82: 2608–2619. https://doi.org/10.1021/acs.jnatprod.9b00549

48. Meickle T, Matthew S, Ross C, et al., 2009, Bioassay-guided isolation and identification of desacetylmicrocolin B from Lyngbya cf. polychroa. Planta Med, 75: 1427–1430. https://doi.org/10.1055/s-0029-1185675

49. Ding L, Bar-Shalom R, Aharonovich D, et al., 2021, Metabolomic characterization of a cf. Neolyngbya cyanobacterium from the South China sea reveals wenchangamide a, a lipopeptide with in vitro apoptotic potential in colon cancer cells. Mar Drugs, 19: 397. https://doi.org/10.3390/md19070397

50. Suntornchashwej S, Chaichit N, Isobe M, et al., 2005, Hectochlorin and morpholine derivatives from the Thai sea hare, Bursatella leachii. J Nat Prod, 68: 951–955. https://doi.org/10.1021/np0500124

51. Marquez BL, Watts KS, Yokochi A, et al., 2002, Structure and absolute stereochemistry of hectochlorin, a potent stimulator of actin assembly. J Nat Prod, 65: 866–871. https://doi.org/10.1021/np0106283

52. Amin N, Kannaujiya VK, 2021, Metabolic pathways for production of anticancer compounds in Cyanobacteria. In: Evolutionary Diversity as a Source for Anticancer Molecules. United States: Academic Press, p127–154.

53. Cai W, Matthew S, Chen QY, et al., 2018, Discovery of new A- and B-type laxaphycins with synergistic anticancer activity. Bioorg Med Chem, 26: 2310–2319. https://doi.org/10.1016/j.bmc.2018.03.022

54. Perera RMTD, Herath KHINM, Sanjeewa KKA, et al., 2023, Recent reports on bioactive compounds from marine Cyanobacteria in relation to human health applications R. Life (Basel), 13: 1411. https://doi.org/10.3390/life1306141

55. Kwan JC, Taori K, Paul VJ, et al., 2009, Lyngbyastatins 8-10, elastase inhibitors with cyclic depsipeptide scaffolds isolated from the marine cyanobacterium Lyngbya semiplena. Mar Drugs, 7: 528–538. https://doi.org/10.3390/md7040528

56. Matthew S, Ross C, Rocca JR, et al., 2007, Lyngbyastatin 4, a dolastatin 13 analogue with elastase and chymotrypsin inhibitory activity from the marine cyanobacterium Lyngbya confervoides. J Nat Prod, 70: 124–127. https://doi.org/10.1021/np060471k

57. Choi H, Mevers E, Byrum T, et al., 2012, Lyngbyabellins K-N from two Palmyra atoll collections of the marine cyanobacterium Moorea bouillonii. European J Org Chem, 2012: 5141–5150. https://doi.org/10.1002/ejoc.201200691

58. Mondal A, Bose S, Banerjee S, et al., 2020, Marine Cyanobacteria and microalgae metabolites--a rich source of potential anticancer drugs. Mar Drugs, 18: 476. https://doi.org/10.3390/md18090476

59. Baur P, Kühl M, Comba P, et al., 2022, Possible functional roles of patellamides in the ascidian-prochloron symbiosis. Mar Drugs, 20: 119. https://doi.org/10.3390/md20020119

60. Kawaguchi M, Satake M, Zhang BT, et al., 2020, Neo-aplysiatoxin A isolated from Okinawan cyanobacterium Moorea producens. Molecules, 25: 457. https://doi.org/10.3390/molecules25030457

61. Ohno O, Iwasaki A, Same K, et al., 2022, Isolation of caldorazole, a thiazole-containing polyketide with selective cytotoxicity under glucose-restricted conditions. Org Lett, 24: 4547–4551. https://doi.org/10.1021/acs.orglett.2c01566

62. Kurisawa N, Iwasaki A, Teranuma K, et al., 2022, Structural determination, total synthesis, and biological activity of iezoside, a highly potent Ca2+-ATPase inhibitor from the marine cyanobacterium Leptochromothrix valpauliae. J Am Chem Soc, 144: 11019–11032. https://doi.org/10.1021/jacs.2c04459

63. Wunder A, Rothemund M, Schobert R, 2018, Synthesis and anticancer activity of the proposed structure of caldoramide, an N-peptidyltetramate from the cyanobacterium Caldora penicillata. Tetrahedron, 74: 5138–5142.