A Prodrug of Two Approved Drugs, Cisplatin and Chlorambucil, for Chemo War Against Cancer.
Cancer cells maintain normal mitochondrial glutathione as one of the defense mechanisms to inhibit mitochondrial membrane polarization and hence apoptosis. A combinational therapeutic modality Platin-Cbl, a prodrug of FDA-approved chemotherapeutic agents, cisplatin and chlorambucil (Cbl), was synthesized and characterized to explore the potential of this compound to initiate chemo war on cancer cells using the active drugs, cisplatin and Cbl, when delivered to the cellular power house mitochondrion using a targeted nanoparticle designed to get associated with this organelle. Platin-Cbl demonstrated significantly high cytotoxic activity across a number of tumor cell lines as well as in a cisplatin-resistant cancer cell line compared with cisplatin or its mixture with Cbl suggesting its unique potency in cisplatin-resistant tumors. A mitochondria-targeted nanoparticle formulation of Platin-Cbl allowed for its efficacious mitochondrial delivery.In vitrostudies documented high potency of Platin-Cbl nanoparticle formulations. Cisplatin-resistant cells upon treatment with Platin-Cbl were still able to manage energy production to a certain extent via fatty acid pathway; the advantage of using T-Platin-Cbl-NP is that this nanoparticle treatment causes impairment of all metabolic pathways in cisplatin-resistant cells forcing the cells to undergo efficient apoptosis. This study highlights a combination of several beneficial effects for a cascade of events to overcome resistance associated with single drug therapy.Mol Cancer Ther; 16(4); 625-36. ©2017 AACR.
Department of Chemistry, University of Georgia, Athens, Georgia.
Rakesh K
RK
Pathak
Department of Biochemistry and Molecular Biology Miller School of Medicine, University of Miami, Miami, Florida.
Ru
R
Wen
Partikula LLC, Sunrise, Florida.
Nagesh
N
Kolishetti
Department of Chemistry, University of Georgia, Athens, Georgia. shantadhar@med.miami.edu.|Department of Biochemistry and Molecular Biology Miller School of Medicine, University of Miami, Miami, Florida.|Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
Shanta
S
Dhar
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002699:Chlorambucil / Q000737:chemistry* / Q000494:pharmacology; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D053758:Nanoparticles / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D005227:Fatty Acids; D011355:Prodrugs; D002699:Chlorambucil; D002945:Cisplatin