Abstract
On the basis of enhanced tumor accumulation and bone affinity, gallium compounds are under development as anticancer and antimetastatic agents. In this study, we analyzed molecular targets of one of the lead anticancer gallium complexes [KP46, Tris(8-quinolinolato)gallium(III)] focusing on colon and lung cancer. Within a few hours, KP46 treatment at low micromolar concentrations induced cell body contraction and loss of adhesion followed by prompt cell decomposition. This rapid KP46-induced cell death lacked classic apoptotic features and was insensitive toward a pan-caspase inhibitor. Surprisingly, however, it was accompanied by upregulation of proapoptotic Bcl-2 family members. Furthermore, a Bax- but not a p53-knockout HCT-116 subline exhibited significant KP46 resistance. Rapid KP46-induced detachment was accompanied by downregulation of focal adhesion proteins, including several integrin subunits. Loss of integrin-β1 and talin plasma membrane localization corresponded to reduced binding of RGD (Arg-Gly-Asp) peptides to KP46-treated cells. Accordingly, KP46-induced cell death and destabilization of integrins were enhanced by culture on collagen type I, a major integrin ligand. In contrast, KP46-mediated adhesion defects were partially rescued by Mg(2+) ions, promoting integrin-mediated cell adhesion. Focal adhesion dynamics are regulated by calpains via cleavage of multiple cell adhesion molecules. Cotreatment with the cell-permeable calpain inhibitor PD150606 diminished KP46-mediated integrin destabilization and rapid cell death induction. KP46 treatment distinctly inhibited HCT-116 colon cancer xenograft in vivo by causing reduced integrin plasma membrane localization, tissue disintegration, and intense tumor necrosis. This study identifies integrin deregulation via a calpain-mediated mechanism as a novel mode of action for the anticancer gallium compound KP46.
Highlights
Metal compounds have a long history as therapeutic agents, especially in oncology
We decided to focus on these major tumor entities (IC50 values for a cell line panel from these tumor entities are shown in Table 1) and to compare A549 and SW480 as "KP46-resistant" cells in contrast to HCT-116 and A427 as "KP46-sensitive" representatives
We did not find any significant differences in KP46 activity exerted against multiple p53 wild-type and p53-mutated/knockout cancer cell lines (Supplementary Fig. S1A)
Summary
Metal compounds have a long history as therapeutic agents, especially in oncology. since the successful clinical approval of cisplatin, platinum compounds have dominated the field of anticancer metal drug research. Other metals have moved into focus for drug development due to their tumortargeting properties, redox-based activation mechanisms, and unexpected molecular targeting characteristics [1, 2]. Major aims of these attempts are to optimize the therapeutic activity, reduce unwanted adverse effects, and prevent resistance development [3]. The development of gallium compounds for anticancer therapy is especially interesting due to the fact that gallium shares several characteristics with iron. On the basis of the enhanced needs of the rapidly proliferating malignant tissue for iron, gallium compounds harbor intrinsic tumor-targeting properties by preferential uptake via the transferrin/transferrin receptor system [4]. Gallium nitrate has been approved for the treatment
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