Abstract
Reprogramming of energy metabolism is pivotal to cancer, so mitochondria are potential targets for anticancer therapy. A prior study has demonstrated the anti-proliferative activity of a new class of mitochondria-targeting rosamines. This present study describes in vitro cytotoxicity of second-generation rosamine analogs, their mode of action, and their in vivo efficacies in a tumor allografted mouse model. Here, we showed that these compounds exhibited potent cytotoxicity (average IC50<0.5 µM), inhibited Complex II and ATP synthase activities of the mitochondrial oxidative phosphorylation pathway and induced loss of mitochondrial transmembrane potential. A NCI-60 cell lines screen further indicated that rosamine analogs 4 and 5 exhibited potent antiproliferative effects with Log10GI50 = −7 (GI50 = 0.1 µM) and were more effective against a colorectal cancer sub-panel than other cell lines. Preliminary in vivo studies on 4T1 murine breast cancer-bearing female BALB/c mice indicated that treatment with analog 5 in a single dosing of 5 mg/kg or a schedule dosing of 3 mg/kg once every 2 days for 6 times (q2d×6) exhibited only minimal induction of tumor growth delay. Our results suggest that rosamine analogs may be further developed as mitochondrial targeting agents. Without a doubt proper strategies need to be devised to enhance tumor uptake of rosamines, i.e. by integration to carrier molecules for better therapeutic outcome.
Highlights
Conventional cancer chemotherapy depends on drugs that act by interrupting DNA replication, i.e. by inhibiting the synthesis or function of new nucleic materials, or by causing irreparable damage to vital nucleic acids through intercalation, alkylation or enzymatic inhibition
Mitochondria-targeting drugs interfere with cancer cell metabolisms by pertubing the mitochondrial transmembrane potential, inhibiting the electron redox chain complexes, interfering the mitochondria transmembrane permeability, and targeting mitochondrial-DNA [6,7]
Rosamine Analogs Our previous study indicated structures meso-substituted with 4
Summary
Conventional cancer chemotherapy depends on drugs that act by interrupting DNA replication, i.e. by inhibiting the synthesis or function of new nucleic materials, or by causing irreparable damage to vital nucleic acids through intercalation, alkylation or enzymatic inhibition. Contemporary chemotherapeutic strategies that target signaling pathways or particular gene products tend to be limited to cancers driven by a dominant oncogene and are often vulnerable to resistance via the multiplicity of tumorigenesis signaling pathways [1]. Mitochondria are the energy generators that maintain cell life and essential cell functions, including multiple signaling cascades that regulate cells, for instance, metabolism, cell cycle control, development, and cell death [5]. Mitochondria-targeting drugs interfere with cancer cell metabolisms by pertubing the mitochondrial transmembrane potential, inhibiting the electron redox chain complexes, interfering the mitochondria transmembrane permeability, and targeting mitochondrial-DNA [6,7]. The most common types of mitochondria-targeting drugs are lipophilic, cationic drugs; these are selective for cancer cells because they tend to have higher mitochondrial membrane potentials than normal epithelial cells [8,9]
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