Abstract
Cardiac glycosides could increase intracellular Ca2+ ion by inhibiting the Na+/K+ATPase to induce apoptosis in many tumor cells. However, narrow therapeutic index, poor tumor selectivity and severe cardiovascular toxicity hinder their applications in cancer treatment. To improve the safety profile and tumor targetablility of cardiac glycosides, we designed octreotide conjugated periplocymarin, a cardiac glycoside isolated from Cortex periplocae. The conjugate showed higher cytotoxicity on MCF-7 cells and HepG2 tumor cells (SSTRs overexpression) but much less toxicity in L-02 normal cells. Tissue distribution studies of the conjugate using H22 tumor model in mice showed higher accumulation in tumor and lower distribution in heart and liver than periplocymarin. Furthermore, in vivo anticancer effects of the conjugate on mice bearing H22 cancer xenografts confirmed enhanced anti-tumor efficacy and decreased systemic toxicity. Altogether, octreotide-conjugated periplocymarin demonstrated tumor selectivity and may be useful as a targeting agent to improve the safety profile of cardiac glycosides for cancer therapy.
Highlights
Cardiac steroids (CS) or cardiotonic glycosides represent a group of compounds used clinically to increase cardiac contractile force in patients with congestive heart failure and cardiac arrhythmias [1, 2]
A number of publications have emphasized that apoptosis produced by cardiotonic glycosides in human tumor cells could be achieved at concentrations with no toxicity in humans, and these agents might be useful for cancer treatment [3, 4]
The electrospray ionization mass spectrometry (ESI–MS) result gave [M+H]+ mass/ charge (m/z) value of 635.45 Da, the 1H-NMR spectra yielded δ: 2.6 (t, succinic anhydride 2 CH2, 4H) and 13C-NMR spectra produced δ:174.82, 171.68, 29.012, 28.72. These results showed that SPPM was successfully synthesized
Summary
Cardiac steroids (CS) or cardiotonic glycosides represent a group of compounds used clinically to increase cardiac contractile force in patients with congestive heart failure and cardiac arrhythmias [1, 2]. A number of publications have emphasized that apoptosis produced by cardiotonic glycosides in human tumor cells could be achieved at concentrations with no toxicity in humans, and these agents might be useful for cancer treatment [3, 4]. The classic CS appear to lack sufficient anti-tumor activity to be used as single anti-cancer agents at clinically acceptable doses [5]. Periplocymarin showed more cytotoxicity than the reference compounds (ouabain, periplogenin and periplocin) and could induce apoptosis in PC3 cells [8]. As a monosaccharide cardiac glycosides, its short elimination half-life, narrow therapeutic index, lack of tumor selectivity and severe adverse effects have hindered its wide applications in cancer treatment [9, 10]. Targeted chemotherapy has become a novel approach to the treatment of cancers due to improved efficacy and reduced toxicity [11, 12]
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