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 Food and Drug Administration (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 (NP) 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 to cisplatin or its mixture with Cbl suggesting its unique potency in cisplatin resistant tumors. A mitochondria targeted NP formulation of Platin-Cbl allowed for its efficacious mitochondrial delivery. In vitro studies documented high potency of Platin-Cbl NP formulations. Cisplatin resistant cells 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 NP 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.
- Received July 18, 2016.
- Revision received November 28, 2016.
- Accepted January 3, 2017.
- Copyright ©2017, American Association for Cancer Research.