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Supplementary Figure 1 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Supplementary Figure 6 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Supplementary Figure 4 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Supplementary Table 1, Methods and Materials, Figure Legends 1-6 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Supplementary Figure 5 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Resistance of tumor cells to cisplatin is a common feature frequently encountered during chemotherapy against melanoma caused by various known and unknown mechanisms. To overcome drug resistance toward cisplatin, a targeted treatment using alternative agents, such as proteasome inhibitors, has been investigated. This combination could offer a new therapeutic approach. Here, we report the biological effects of proteasome inhibitors on the parental cisplatin-sensitive MeWo human melanoma cell line and its cisplatin-resistant MeWocis1 variant. Our experiments show that proteasome inhibitor treatment of both cell lines impairs cell viability at concentrations that are not toxic to primary human fibroblasts in vitro. However, compared with the parental MeWo cell line, significantly higher concentrations of proteasome inhibitor are required to reduce cell viability of MeWocis1 cells. Moreover, whereas proteasome activity was inhibited to the same extent in both cell lines, IκBα degradation and nuclear factor-κB (NF-κB) activation in MeWocis1 cells was proteasome inhibitor independent but essentially calpain inhibitor sensitive. In support, a calpain-specific inhibitor impaired NF-κB activation in MeWocis1 cells. Here, we show that cisplatin resistance in MeWocis1 is accompanied by a change in the NF-κB activation pathway in favor of calpain-mediated IκBα degradation. Furthermore, combined exposure to proteasome and calpain inhibitor resulted in additive effects and a strongly reduced cell viability of MeWocis1 cells. Thus, combined strategies targeting distinct proteolytic pathways may help to overcome mechanisms of drug resistance in tumor cells. (Cancer Res 2006; 66(15): 7598-605)

Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity toward tumor cells by inducing production of reactive oxygen species such as singlet oxygen. PDT leads to oxidative damage of cellular macromolecules, including proteins that undergo multiple modifications such as fragmentation, cross-linking, and carbonylation that result in protein unfolding and aggregation. Because the major mechanism for elimination of carbonylated proteins is their degradation by proteasomes, we hypothesized that a combination of PDT with proteasome inhibitors might lead to accumulation of carbonylated proteins in endoplasmic reticulum (ER), aggravated ER stress, and potentiated cytotoxicity toward tumor cells. We observed that Photofrin-mediated PDT leads to robust carbonylation of cellular proteins and induction of unfolded protein response. Pretreatment of tumor cells with three different proteasome inhibitors, including bortezomib, MG132, and PSI, gave increased accumulation of carbonylated and ubiquitinated proteins in PDT-treated cells. Proteasome inhibitors effectively sensitized tumor cells of murine (EMT6 and C-26) as well as human (HeLa) origin to PDT-mediated cytotoxicity. Significant retardation of tumor growth with 60% to 100% complete responses was observed in vivo in two different murine tumor models (EMT6 and C-26) when PDT was combined with either bortezomib or PSI. Altogether, these observations indicate that combination of PDT with proteasome inhibitors leads to potentiated antitumor effects. The results of these studies are of immediate clinical application because bortezomib is a clinically approved drug that undergoes extensive clinical evaluations for the treatment of solid tumors. [Cancer Res 2009;69(10):4235–43]

Supplementary Figure 2 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Supplementary Figure 3 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Supplementary Figure 2 from Combined Effect of Proteasome and Calpain Inhibition on Cisplatin-Resistant Human Melanoma Cells

Supplementary Figure 1 from Combined Effect of Proteasome and Calpain Inhibition on Cisplatin-Resistant Human Melanoma Cells

Cancer is one of the leading causes of morbidity and mortality worldwide. Colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the second in women. Standard patterns of antitumor therapy, including cisplatin, are ineffective due to their lack of specificity for tumor cells, development of drug resistance, and severe side effects. For this reason, new methods and strategies for CRC treatment are urgently needed. Current research includes novel platinum (Pt)- and other metal-based drugs such as gold (Au), silver (Ag), iridium (Ir), or ruthenium (Ru). Au(III) compounds are promising drug candidates for CRC treatment due to their structural similarity to Pt(II). Their advantage is their relatively good solubility in water, but their disadvantage is an unsatisfactory stability under physiological conditions. Due to these limitations, work is still underway to improve the formula of Au(III) complexes by combining with various types of ligands capable of stabilizing the Au(III) cation and preventing its reduction under physiological conditions. This review summarizes the achievements in the field of stable Au(III) complexes with potential cytotoxic activity restricted to cancer cells. Moreover, it has been shown that not nucleic acids but various protein structures such as thioredoxin reductase (TrxR) mediate the antitumor effects of Au derivatives. The state of the art of the in vivo studies so far conducted is also described.