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Cyanobacteria produce a variety of chemically diverse cyclic lipopeptides with potent antifungal activities. These cyclic lipopeptides have an amphipathic structure comprised of a polar peptide cycle and hydrophobic fatty acid side chain. Many have antibiotic activity against a range of human and plant fungal pathogens. This review article aims to summarize the present knowledge on the chemical diversity and cellular effects of cyanobacterial cyclic lipopeptides that display antifungal activity. Cyclic antifungal lipopeptides from cyanobacteria commonly fall into four structural classes; hassallidins, puwainaphycins, laxaphycins, and anabaenolysins. Many of these antifungal cyclic lipopeptides act through cholesterol and ergosterol-dependent disruption of membranes. In many cases, the cyclic lipopeptides also exert cytotoxicity in human cells, and a more extensive examination of their biological activity and structure–activity relationship is warranted. The hassallidin, puwainaphycin, laxaphycin, and anabaenolysin structural classes are unified through shared complex biosynthetic pathways that encode a variety of unusual lipoinitiation mechanisms and branched biosynthesis that promote their chemical diversity. However, the biosynthetic origins of some cyanobacterial cyclic lipopeptides and the mechanisms, which drive their structural diversification in general, remain poorly understood. The strong functional convergence of differently organized chemical structures suggests that the production of lipopeptide confers benefits for their producer. Whether these benefits originate from their antifungal activity or some other physiological function remains to be answered in the future. However, it is clear that cyanobacteria encode a wealth of new cyclic lipopeptides with novel biotechnological and therapeutic applications.
David P. Fewer; Jouni Jokela; Lassi Heinilä; Reidun Aesoy; Kaarina Sivonen; Tomáš Galica; Pavel Hrouzek; Lars Herfindal. Chemical diversity and cellular effects of antifungal cyclic lipopeptides from cyanobacteria. Physiologia Plantarum 2021, 1 .
AMA StyleDavid P. Fewer, Jouni Jokela, Lassi Heinilä, Reidun Aesoy, Kaarina Sivonen, Tomáš Galica, Pavel Hrouzek, Lars Herfindal. Chemical diversity and cellular effects of antifungal cyclic lipopeptides from cyanobacteria. Physiologia Plantarum. 2021; ():1.
Chicago/Turabian StyleDavid P. Fewer; Jouni Jokela; Lassi Heinilä; Reidun Aesoy; Kaarina Sivonen; Tomáš Galica; Pavel Hrouzek; Lars Herfindal. 2021. "Chemical diversity and cellular effects of antifungal cyclic lipopeptides from cyanobacteria." Physiologia Plantarum , no. : 1.
Cyanobacteria are photosynthetic organisms that produce a large diversity of natural products with interesting bioactivities for biotechnological and pharmaceutical applications. Cyanobacterial extracts exhibit toxicity towards other microorganisms and cancer cells and, therefore, represent a source of potentially novel natural products for drug discovery. We tested 62 cyanobacterial strains isolated from various Brazilian biomes for antileukemic and antimicrobial activities. Extracts from 39 strains induced selective apoptosis in acute myeloid leukemia (AML) cancer cell lines. Five of these extracts also exhibited antifungal and antibacterial activities. Chemical and dereplication analyses revealed the production of nine known natural products. Natural products possibly responsible for the observed bioactivities and five unknown, chemically related chlorinated compounds present only in Brazilian cyanobacteria were illustrated in a molecular network. Our results provide new information on the vast biosynthetic potential of cyanobacteria isolated from Brazilian environments.
Tania Keiko Shishido; Rafael Vicentini Popin; Jouni Jokela; Matti Wahlsten; Marli Fatima Fiore; David P. Fewer; Lars Herfindal; Kaarina Sivonen. Dereplication of Natural Products with Antimicrobial and Anticancer Activity from Brazilian Cyanobacteria. Toxins 2019, 12, 12 .
AMA StyleTania Keiko Shishido, Rafael Vicentini Popin, Jouni Jokela, Matti Wahlsten, Marli Fatima Fiore, David P. Fewer, Lars Herfindal, Kaarina Sivonen. Dereplication of Natural Products with Antimicrobial and Anticancer Activity from Brazilian Cyanobacteria. Toxins. 2019; 12 (1):12.
Chicago/Turabian StyleTania Keiko Shishido; Rafael Vicentini Popin; Jouni Jokela; Matti Wahlsten; Marli Fatima Fiore; David P. Fewer; Lars Herfindal; Kaarina Sivonen. 2019. "Dereplication of Natural Products with Antimicrobial and Anticancer Activity from Brazilian Cyanobacteria." Toxins 12, no. 1: 12.
Hassallidins are cyclic glycolipopeptides produced by cyanobacteria and other prokaryotes. The hassallidin structure consists of a peptide ring of eight amino acids where a fatty acid chain, additional amino acid, and sugar moieties are attached. Hassallidins show antifungal activity against several opportunistic human pathogenic fungi, but does not harbor antibacterial effects. However, they have not been studied on mammalian cells, and the mechanism of action is unknown. We purified hassallidin D from cultured cyanobacterium Anabaena sp. UHCC 0258 and characterized its effect on mammalian and fungal cells. Ultrastructural analysis showed that hassallidin D disrupts cell membranes, causing a lytic/necrotic cell death with rapid presence of disintegrated outer membrane, accompanied by internalization of small molecules such as propidium iodide into the cells. Furthermore, artificial liposomal membrane assay showed that hassallidin D selectively targets sterol-containing membranes. Finally, in silico membrane modeling allowed us to study the interaction between hassallidin D and membranes in detail, and confirm the role of cholesterol for hassallidin-insertion into the membrane. This study demonstrates the mechanism of action of the natural compound hassallidin, and gives further insight into how bioactive lipopeptide metabolites selectively target eukaryotic cell membranes.
Anu Humisto; Jouni Jokela; Knut Teigen; Matti Wahlsten; Perttu Permi; Kaarina Sivonen; Lars Herfindal. Characterization of the interaction of the antifungal and cytotoxic cyclic glycolipopeptide hassallidin with sterol-containing lipid membranes. Biochimica et Biophysica Acta (BBA) - Biomembranes 2019, 1861, 1510 -1521.
AMA StyleAnu Humisto, Jouni Jokela, Knut Teigen, Matti Wahlsten, Perttu Permi, Kaarina Sivonen, Lars Herfindal. Characterization of the interaction of the antifungal and cytotoxic cyclic glycolipopeptide hassallidin with sterol-containing lipid membranes. Biochimica et Biophysica Acta (BBA) - Biomembranes. 2019; 1861 (8):1510-1521.
Chicago/Turabian StyleAnu Humisto; Jouni Jokela; Knut Teigen; Matti Wahlsten; Perttu Permi; Kaarina Sivonen; Lars Herfindal. 2019. "Characterization of the interaction of the antifungal and cytotoxic cyclic glycolipopeptide hassallidin with sterol-containing lipid membranes." Biochimica et Biophysica Acta (BBA) - Biomembranes 1861, no. 8: 1510-1521.
More than 40 years ago, the present standard induction therapy for acute myeloid leukemia (AML) was developed. This consists of the metabolic inhibitor cytarabine (AraC) and the cytostatic topoisomerase 2 inhibitor daunorubucin (DNR). In light of the high chance for relapse, as well as the large heterogeneity, novel therapies are needed to improve patient outcome. We have tested the anti-AML activity of 15 novel compounds based on the scaffolds pyrrolo[2,3-a]carbazole-3-carbaldehyde, pyrazolo[3,4-c]carbazole, pyrazolo[4,3-a]phenanthridine or pyrrolo[2,3-g] indazole. The compounds were inhibitors of Pim-kinases, but could also have inhibitory activity against other protein kinases. Ser/Thr kinases like the Pim-kinases have been identified as potential drug targets for AML therapy. The compound VS-II-173 induced AML cell death with EC50 below 5 μM, and was ten times less potent against non-malignant cells. It perturbed Pim kinase mediated AML cell signaling, such as attenuation of Stat5 or MDM2 phosphorylation, and synergized with DNR to induce AML cell death. VS-II-173 induced cell death also in AML patient blasts, including blast carrying high-risk FLT3-ITD mutation. Mutation of nucleophosmin-1 was associated with good response to VS-II-173. In conclusion new scaffolds for potential AML drugs have been explored. The selective activity towards patient AML blasts and AML cell lines of the pyrazolo-analogue VS-II-173 make it a promising drug candidate to be further tested in pre-clinical animal models for AML.
Ronja Bjørnstad; Reidun Aesoy; Øystein Bruserud; Annette K. Brenner; Francis Giraud; Tara Helen Dowling; Gro Gausdal; Pascale Moreau; Stein Ove Døskeland; Fabrice Anizon; Lars Herfindal. A Kinase Inhibitor with Anti-Pim Kinase Activity is a Potent and Selective Cytotoxic Agent Toward Acute Myeloid Leukemia. Molecular Cancer Therapeutics 2019, 18, 567 -578.
AMA StyleRonja Bjørnstad, Reidun Aesoy, Øystein Bruserud, Annette K. Brenner, Francis Giraud, Tara Helen Dowling, Gro Gausdal, Pascale Moreau, Stein Ove Døskeland, Fabrice Anizon, Lars Herfindal. A Kinase Inhibitor with Anti-Pim Kinase Activity is a Potent and Selective Cytotoxic Agent Toward Acute Myeloid Leukemia. Molecular Cancer Therapeutics. 2019; 18 (3):567-578.
Chicago/Turabian StyleRonja Bjørnstad; Reidun Aesoy; Øystein Bruserud; Annette K. Brenner; Francis Giraud; Tara Helen Dowling; Gro Gausdal; Pascale Moreau; Stein Ove Døskeland; Fabrice Anizon; Lars Herfindal. 2019. "A Kinase Inhibitor with Anti-Pim Kinase Activity is a Potent and Selective Cytotoxic Agent Toward Acute Myeloid Leukemia." Molecular Cancer Therapeutics 18, no. 3: 567-578.
Okadaic acid (OA) and microcystin (MC) as well as several other microbial toxins like nodularin and calyculinA are known as tumor promoters as well as inducers of apoptotic cell death. Their intracellular targets are the major serine/threonine protein phosphatases. This review summarizes mechanisms believed to be responsible for the death induction and tumor promotion with focus on the interdependent production of reactive oxygen species (ROS) and activation of Ca2+/calmodulin kinase II (CaM-KII). New data are presented using inhibitors of specific ROS producing enzymes to curb nodularin/MC-induced liver cell (hepatocyte) death. They indicate that enzymes of the arachidonic acid pathway, notably phospholipase A2, 5-lipoxygenase, and cyclooxygenases, may be required for nodularin/MC-induced (and presumably OA-induced) cell death, suggesting new ways to overcome at least some aspects of OA and MC toxicity.
Rune Kleppe; Lars Herfindal; Stein Ove Døskeland. Cell Death Inducing Microbial Protein Phosphatase Inhibitors—Mechanisms of Action. Marine Drugs 2015, 13, 6505 -6520.
AMA StyleRune Kleppe, Lars Herfindal, Stein Ove Døskeland. Cell Death Inducing Microbial Protein Phosphatase Inhibitors—Mechanisms of Action. Marine Drugs. 2015; 13 (10):6505-6520.
Chicago/Turabian StyleRune Kleppe; Lars Herfindal; Stein Ove Døskeland. 2015. "Cell Death Inducing Microbial Protein Phosphatase Inhibitors—Mechanisms of Action." Marine Drugs 13, no. 10: 6505-6520.
Frode Selheim; Lars Herfindal. EDITORIAL: Toward Personalized Treatment for Acute Myeloid Leukemia. Current Pharmaceutical Biotechnology 2015, 16, 1 -1.
AMA StyleFrode Selheim, Lars Herfindal. EDITORIAL: Toward Personalized Treatment for Acute Myeloid Leukemia. Current Pharmaceutical Biotechnology. 2015; 16 (999):1-1.
Chicago/Turabian StyleFrode Selheim; Lars Herfindal. 2015. "EDITORIAL: Toward Personalized Treatment for Acute Myeloid Leukemia." Current Pharmaceutical Biotechnology 16, no. 999: 1-1.