Cardamonin is a polyphenolic natural product that has been shown to possess cytotoxic activity against a variety of cancer cell lines. We previously reported the semi-synthesis of a novel Cu (II)-cardamonin complex (19) that demonstrated potent antitumour activity. In this study, we further investigated the bioactivity of 19 against MDA-MB-468 and PANC-1 cancer cells in an attempt to discover an effective treatment for triple-negative breast cancer (TNBC) and pancreatic cancer, respectively. Results revealed that 19 abolished the formation of MDA-MB-468 and PANC-1 colonies, exerted growth-inhibitory activity, and inhibited cancer cell migration. Further mechanistic studies showed that 19 induced DNA damage resulting in gap 2 (G2)/mitosis (M) phase arrest and microtubule network disruption. Moreover, 19 generated reactive oxygen species (ROS) that may contribute to induction of apoptosis, corroborated by activation of caspase-3/7, PARP cleavage, and downregulation of Mcl-1. Complex 19 also decreased the expression levels of p-Akt and p-4EBP1, which indicates that the compound exerts its activity, at least in part, via inhibition of Akt signalling. Furthermore, 19 decreased the expression of c-Myc in PANC-1 cells only, which suggests that it may exert its bioactivity via multiple mechanisms of action. These results demonstrate the potential of 19 as a therapeutic agent for TNBC and pancreatic cancer.
The O-acetyl (or acetate) derivative of the Aspidosperma alkaloid Jerantinine A (JAa) elicits anti-tumor activity against cancer cell lines including mammary carcinoma cell lines irrespective of receptor status (0.14 < GI50 < 0.38 μM), targeting microtubule dynamics. By exploiting breast cancer cells' upregulated transferrin receptor 1 (TfR1) expression and apoferritin (AFt) recognition, we sought to develop an AFt JAa-delivery vehicle to enhance tumor-targeting and reduce systemic toxicity. Optimizing pH-mediated reassembly, ∼120 JAa molecules were entrapped within AFt. Western blot and flow cytometry demonstrate TfR1 expression in cancer cells. Enhanced internalization of 5-carboxyfluorescein-conjugated human AFt in SKBR3 and MDA-MB-231 cancer cells is observed compared to MRC5 fibroblasts. Accordingly, AFt-JAa delivers significantly greater intracellular JAa levels to SKBR3 and MDA-MB-231 cells than naked JAa (0.2 μM) treatment alone. Compared to naked JAa (0.2 μM), AFt-JAa achieves enhanced growth inhibition (2.5-14-fold; <0.02 μM < GI50 < 0.15 μM) in breast cancer cells; AFt-JAa treatment results in significantly reduced clonal survival, more profound cell cycle perturbation including G2/M arrest, greater reduction in cell numbers, and increased apoptosis compared to the naked agent (p < 0.01). Decreased PLK1 and Mcl-1 expression, together with the appearance of cleaved poly (ADP-ribose)-polymerase, corroborate the augmented potency of AFt-JAa. Hence, we demonstrate that AFt represents a biocompatible vehicle for targeted delivery of JAa, offering potential to minimize toxicity and enhance JAa activity in TfR1-expressing tumors.
Natural products possess a significant role in anticancer therapy and many currently-used anticancer drugs are of natural origin. Cerberin (CR), a cardenolide isolated from the fruit kernel of Cerbera odollam, was found to potently inhibit cancer cell growth (GI50 values 60% bioavailability and rapid absorption; doses of 1-10 mg/kg CR were predicted to maintain efficacious unbound plasma concentrations (>GI50 value). CR's potent and selective anti-tumour activity, and its targeting of key signalling mechanisms pertinent to tumourigenesis support further preclinical evaluation of this cardiac glycoside.