TY - JOUR
T1 - Mitochondrial Relocation of a Common Synthetic Antibiotic
T2 - A Non-genotoxic Approach to Cancer Therapy
AU - Sunwoo, Kyoung
AU - Won, Miae
AU - Ko, Kyung Phil
AU - Choi, Miri
AU - Arambula, Jonathan F.
AU - Chi, Sung Gil
AU - Sessler, Jonathan L.
AU - Verwilst, Peter
AU - Kim, Jong Seung
N1 - Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) ( 2018R1A2A1A05020236 to S.-G.C. and CRI project no. 2018R1A3B1052702 to J.S.K.) and funded by the Basic Science Research Program of the NRF ( 2017R1D1A1B03032561 to P.V. and 2017R1D1A1B03030062 to M.W.) and the Ministry of Education and the Korea Research Fellowship Program of the NRF ( 2016H1D3A1938052 to P.V.). K.S. is a recipient of the Global PhD Fellowship (GPF) program, funded by the NRF ( 2014H1A2A1020978 ). Funding from the National Cancer Institute of the United States (RO1 CA68682 to J.L.S. and R15 CA232765 to J.F.A.) for the support in Austin is acknowledged.
Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) (2018R1A2A1A05020236 to S.-G.C. and CRI project no. 2018R1A3B1052702 to J.S.K.) and funded by the Basic Science Research Program of the NRF (2017R1D1A1B03032561 to P.V. and 2017R1D1A1B03030062 to M.W.) and the Ministry of Education and the Korea Research Fellowship Program of the NRF (2016H1D3A1938052 to P.V.). K.S. is a recipient of the Global PhD Fellowship (GPF) program, funded by the NRF (2014H1A2A1020978). Funding from the National Cancer Institute of the United States (RO1 CA68682 to J.L.S. and R15 CA232765 to J.F.A.) for the support in Austin is acknowledged. K.S. contributed to synthesis, characterization, and solution experiments; M.W. and K.-P.K. conducted biological experiments; M.W. performed statistical analyses; P.V. K.S. M.W. J.F.A. and J.L.S. contributed to writing, review, and editing; K.S. M.W. S.-G.C. P.V. J.F.A. J.L.S. and J.S.K. received study-enabling funding; K.S. P.V. and J.S.K. contributed to initial project conception; S.-G.C. J.L.S. P.V. J.F.A. and J.S.K. contributed to supervision and project development. All authors proofread, commented on, and approved the final version of the manuscript. Mt-CFX and analogs as non-genotoxic anticancer agents are the subject of a pending patent application, filed by Korea University, with J.S.K, K.S. P.V. and M.W. named as inventors. J.L.S. holds a part-time summer position at Shanghai University.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/6/11
Y1 - 2020/6/11
N2 - Tumor recurrence as a result of therapy-induced nuclear DNA lesions is a major issue in cancer treatment. Currently, only a few examples of potentially non-genotoxic drugs have been reported. Mitochondrial re-localization of ciprofloxacin, one of the most commonly prescribed synthetic antibiotics, is reported here as a new approach. Conjugation of ciprofloxacin to a triphenyl phosphonium group (giving lead Mt-CFX) is used to enhance the concentration of ciprofloxacin in the mitochondria of cancer cells. The localization of Mt-CFX to the mitochondria induces oxidative damage to proteins, mtDNA, and lipids. A large bias in favor of mtDNA damage over nDNA was seen with Mt-CFX, contrary to classic cancer chemotherapeutics. Mt-CFX was found to reduce cancer growth in a xenograft mouse model and proved to be well tolerated. Mitochondrial re-localization of antibiotics could emerge as a useful approach to generating anticancer leads that promote cell death via the selective induction of mitochondrially mediated oxidative damage.
AB - Tumor recurrence as a result of therapy-induced nuclear DNA lesions is a major issue in cancer treatment. Currently, only a few examples of potentially non-genotoxic drugs have been reported. Mitochondrial re-localization of ciprofloxacin, one of the most commonly prescribed synthetic antibiotics, is reported here as a new approach. Conjugation of ciprofloxacin to a triphenyl phosphonium group (giving lead Mt-CFX) is used to enhance the concentration of ciprofloxacin in the mitochondria of cancer cells. The localization of Mt-CFX to the mitochondria induces oxidative damage to proteins, mtDNA, and lipids. A large bias in favor of mtDNA damage over nDNA was seen with Mt-CFX, contrary to classic cancer chemotherapeutics. Mt-CFX was found to reduce cancer growth in a xenograft mouse model and proved to be well tolerated. Mitochondrial re-localization of antibiotics could emerge as a useful approach to generating anticancer leads that promote cell death via the selective induction of mitochondrially mediated oxidative damage.
KW - DNA damage
KW - SDG3: Good health and well-being
KW - ciprofloxacin
KW - mitochondria
KW - non-genotoxic cancer therapy
KW - prodrug
KW - reactive oxygen species
KW - targeted therapeutics
UR - http://www.scopus.com/inward/record.url?scp=85083007577&partnerID=8YFLogxK
U2 - 10.1016/j.chempr.2020.03.004
DO - 10.1016/j.chempr.2020.03.004
M3 - Article
AN - SCOPUS:85083007577
SN - 2451-9294
VL - 6
SP - 1408
EP - 1419
JO - Chem
JF - Chem
IS - 6
ER -
