The actin cytoskeleton is a potentially vulnerable property of cancer cells, yet chemotherapeutic targeting attempts have been hampered by unacceptable toxicity. In this study, we have shown that it is possible to disrupt specific actin filament populations by targeting isoforms of tropomyosin, a core component of actin filaments, that are selectively upregulated in cancers. A novel class of anti-tropomyosin compounds has been developed that preferentially disrupts the actin cytoskeleton of tumor cells, impairing both tumor cell motility and viability. Our lead compound, TR100, is effective in vitro and in vivo in reducing tumor cell growth in neuroblastoma and melanoma models. Importantly, TR100 shows no adverse impact on cardiac structure and function, which is the major side effect of current anti-actin drugs. This proof-of-principle study shows that it is possible to target specific actin filament populations fundamental to tumor cell viability based on their tropomyosin isoform composition. This improvement in specificity provides a pathway to the development of a novel class of anti-actin compounds for the potential treatment of a wide variety of cancers. Cancer Res; 73(16); 5169-82. Ó2013 AACR.

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A previous study in the hairless mouse, in which the photoimmune protective properties of a topical phytoestrogen or 17-beta-estradiol were abrogated by the estrogen receptor antagonist ICI 182,780, revealed that estrogen receptor (Er) signaling is involved in the regulation of the suppression of immune function by UVB (290-320 nm) radiation. Here we identify the expression of Er-beta but not Er-alpha mRNA in hairless mouse skin, whereas Er-alpha and Er-beta mRNA were present in normal haired mouse skin. This suggests that the non-classical estrogen target Er-beta is involved in the photoimmune modulation, and is consistent with Er-alpha being more closely associated with hair growth control, as indicated by other studies. In mice with a null mutation for Er-beta, there was a significant exacerbation of the solar simulated UV (290-400 nm)-induced suppression of contact hypersensitivity. Immunohistochemical analysis revealed that the Er-beta deficiency inhibited the normally immunoprotective upregulation by the UVA (320-400 nm) waveband of the epidermal expression of the cytokines IFN-gamma and IL-12. Er-beta deficiency also significantly increased the UVB-induced expression of the immunosuppressive cytokine IL-10. Thus Er signalling via the Er-beta is evidently a major regulator of the UVA and UVB waveband interactions that determine the skin's immune functional status, and achieves this by normalization of the cutaneous cytokine array in the UV-irradiated skin.

Exposure of the skin of mice to UVA (320-400 nm) radiation has been shown to provide protection against the immunosuppressive effects of UVB (290-320 nm) radiation. The UVA protection was mediated via the UVA induction of the stress protein heme oxygenase-1, and its enzymatic product carbon monoxide (CO). Because UVB-induced immunosuppression is an accompanying and prerequisite feature of the promotion phase of photocarcinogenesis, the potential for immunoprotective CO to act as an anti-skin cancer agent was tested in this study. Groups of female albino Skh:hr-1 hairless mice were irradiated chronically with daily minimally erythemogenic doses of solar simulated UV radiation (SSUV) during a 10 week-period to induce photocarcinogenesis. The effect of repeated topical application of lotions containing a CO-releasing molecule (CORM-2; tricarbonyldichlororuthenium (II) dimer) at 250 or 500 microM, that had previously been shown in short-term experiments to provide photoimmune protection in mice, was measured. Tumor development was monitored for 29 weeks. Topical CORM-2 treatment was observed to reduce the acute and chronic inflammatory erythema reaction compared with control irradiated mice that did not receive CORM-2 lotions, and to reduce the chronic epidermal hyperplasia accompanying tumor outgrowth. The CORM-2 treatments provided a significant moderate inhibition of early tumor appearance dose-dependently, significantly reduced the average tumor multiplicity, increased the regression of established tumors dose-dependently, and inhibited the formation of large locally invasive tumors. The CORM-2 treatments also reduced the expression of immunosuppressive IL-10 in the uninvolved epidermis and dermis of tumor-bearing mice, and enhanced immunopotentiating epidermal IL-12 expression. Therefore CO signalling was revealed to have previously unrecognized anti-carcinogenic functions in the skin, consistent with a protective modulation of the epidermal cytokines. This is a novel observation that also implies that the UVA waveband that produces CO physiologically in exposed skin, might likewise be found to have an anti-photocarcinogenic action.

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