Dual-Activity Fluoroquinolone-Transportan 10 Conjugates Offer Alternative Leukemia Therapy during Hematopoietic Cell Transplantation.

Autor:	Lica JJ; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Heldt M; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Wieczór M; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Chodnicki P; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Ptaszyńska N; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Maciejewska N; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Łęgowska A; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Brankiewicz W; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Gucwa K; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Stupak A; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Pradhan B; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Gitlin-Domagalska A; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Dębowski D; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Milewski S; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Bieniaszewska M; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Grabe GJ; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Hellmann A; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.)., Rolka K; Department of Regenerative Medicine, Faculty of Medicine, Medical University of Warsaw, Poland (J.J.L.); Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry (M.H., N.M., S.M.) and Department of Physical Chemistry, Faculty of Chemistry, (M.W., P.C.) Gdansk University of Technology, Poland; Department of Molecular Biochemistry, Faculty of Chemistry, University of Gdansk, Poland (J.J.L., N.P., A.Ł., A.G.-D., D.D., K.R.); Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Norway (W.B.); Department of Microbiology, Faculty of Biology, University of Gdansk, Poland (K.G.); Polpharma Biologics S.A. Gdansk Science and Technology Park, Poland (A.S.); Department of Biochemistry, Faculty of Pharmacy, Medical University of Warsaw, Poland (B.P.); Medical University of Gdansk, Faculty of Medicine, Department of Hematology and Transplantology, Poland (M.B., A.H.); and Structural Biology Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland (G.J.G.).
Jazyk:	angličtina
Zdroj:	Molecular pharmacology [Mol Pharmacol] 2023 Dec 15; Vol. 105 (1), pp. 39-53. Date of Electronic Publication: 2023 Dec 15.
DOI:	10.1124/molpharm.123.000735
Abstrakt:	Hematopoietic cell transplantation (HCT) is often considered a last resort leukemia treatment, fraught with limited success due to microbial infections, a leading cause of mortality in leukemia patients. To address this critical issue, we explored a novel approach by synthesizing antileukemic agents containing antibacterial substances. This innovative strategy involves conjugating fluoroquinolone antibiotics, such as ciprofloxacin (CIP) or levofloxacin (LVX), with the cell-penetrating peptide transportan 10 (TP10). Here, we demonstrate that the resultant compounds display promising biologic activities in preclinical studies. These novel conjugates not only exhibit potent antimicrobial effects but are also selective against leukemia cells. The cytotoxic mechanism involves rapid disruption of cell membrane asymmetry leading to membrane damage. Importantly, these conjugates penetrated mammalian cells, accumulating within the nuclear membrane without significant effect on cellular architecture or mitochondrial function. Molecular simulations elucidated the aggregation tendencies of TP10 conjugates within lipid bilayers, resulting in membrane disruption and permeabilization. Moreover, mass spectrometry analysis confirmed efficient reduction of disulfide bonds within TP10 conjugates, facilitating release and activation of the fluoroquinolone derivatives. Intriguingly, these compounds inhibited human topoisomerases, setting them apart from traditional fluoroquinolones. Remarkably, TP10 conjugates generated lower intracellular levels of reactive oxygen species compared with CIP and LVX. The combination of antibacterial and antileukemic properties, coupled with selective cytostatic effects and minimal toxicity toward healthy cells, positions TP10 derivatives as promising candidates for innovative therapeutic approaches in the context of antileukemic HCT. This study highlights their potential in search of more effective leukemia treatments. SIGNIFICANCE STATEMENT: Fluoroquinolones are commonly used antibiotics, while transportan 10 (TP10) is a cell-penetrating peptide (CPP) with anticancer properties. In HCT, microbial infections are the primary cause of illness and death. Combining TP10 with fluoroquinolones enhanced their effects on different cell types. The dual pharmacological action of these conjugates offers a promising proof-of-concept solution for leukemic patients undergoing HCT. Strategically designed therapeutics, incorporating CPPs with antibacterial properties, have the potential to reduce microbial infections in the treatment of malignancies. (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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