Abstract
Doxorubicin, a widely used chemotherapeutic drug, has several potential high-risk side effects including cardiomyopathy. Furthermore, cellular resistance to this drug develops with time. By using liposomes as carrier vesicles both the side effects and drug resistance might be avoided. In this study we have investigated the cytotoxic effect of doxorubicin encapsulated in liposomes with and without ceramides containing 6 or 12 carbon atoms in the N-amidated fatty acyl chains. The short-chain ceramide species were included in the liposomal compositions due to their pro-apoptotic properties, which might cause a synergistic anticancer effect. We demonstrate that the ceramide species enhance the liposomal doxorubicin toxicity in a cell-specific manner. The C6-ceramide effect is most pronounced in cervical cancer cells (HeLa) and colon cancer cells (HCT116), whereas the C12-ceramide effect is strongest in breast cancer cells (MDA-MB-231). Moreover, the study reveals the importance of investigating cell toxicity at several time points and in different cell-lines, to assess drug-and formulation-induced cytotoxic effects in vitro. Furthermore, our data show that the cytotoxicity obtained with the nanocarriers in vitro, does not necessarily reflect their ability to inhibit tumor growth in vivo. We speculate that the larger effect of Caelyx® than our liposomes in vivo is due to a greater in vivo stability of Caelyx®.
Highlights
Chemotherapy has improved the prognosis of a number of different cancer diagnoses during the last decades, but unwanted drug effects on healthy tissue remain a major problem
We demonstrate that the ceramide species enhance the liposomal doxorubicin toxicity in a cell-specific manner
The C6-ceramide effect is most pronounced in cervical cancer cells (HeLa) and colon cancer cells (HCT116), whereas the C12-ceramide effect is strongest in breast cancer cells (MDA-MB-231)
Summary
Chemotherapy has improved the prognosis of a number of different cancer diagnoses during the last decades, but unwanted drug effects on healthy tissue remain a major problem. Liposomes are suitable drug carrier systems for therapeutic applications in cancer treatment, and able to incorporate drugs with different physicochemical properties [1, 2]. Liposomes may protect the drug from enzymatic degradation, improve the drug pharmacokinetics, and tissue distribution, and provide a sustained or controlled release of therapeutic agents at appropriate sites [3, 4]. One of the most successful liposome-encapsulated drugs is doxorubicin (DOX), available as the marketed (PEGylated liposomal) product Doxil®/Caelyx® [5, 6], approved by FDA in 1995. Higher susceptibility towards hand-and-foot disease (palmar plantar erythrodysthesia) in patients treated with Doxil®/ Caelyx® [7] drives the investigations towards improved formulations of PEGylated liposomal DOX
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