Enhancing the effects of chemotherapy by combined macrophage-mediated photothermal therapy (PTT) and photochemical internalization (PCI).

Light-based treatment modalities such as photothermal therapy (PTT) or photochemical internalization (PCI) have been well documented both experimentally and clinically to enhance the efficacy of chemotherapy. The main purpose of this study was to examine the cytotoxic effects of silica-gold nanoshell (AuNS)-loaded macrophage-mediated (MaNS) PTT and bleomycin BLM-PCI on monolayers of squamous cell carcinoma cells. The two modalities were applied separately and in simultaneous combination. Two different wavelengths of light were employed simultaneously, one to activate a highly efficient PCI photosensitizer, AlPcS2a (670 nm) and the other for the MaNS-mediated PTT (810 nm), to evaluate the combined effects of these modalities. The results clearly demonstrated that macrophages could ingest sufficient numbers of silica-gold nanoshells for efficient near infrared (NIR) activated PTT. A significant synergistic effect of simultaneously applied combined PTT and PCI, compared to each modality applied separately, was achieved. Light-driven therapies have the advantage of site specificity, non-invasive and non-toxic application, require inexpensive equipment and can be given as repetitive treatment protocols.

Deciphering the Nongenomic, Mitochondrial Toxicity of Tamoxifens As Determined by Cell Metabolism and Redox Activity.

Tamoxifen is not only considered a very potent chemotherapeutic adjuvant for estrogen receptor positive breast cancers but also a very good chemo-preventive drug. Recently, there has been a rising amount of evidence for a nongenomic cytotoxicity of tamoxifen, even in estrogen receptor negative cells, which has greatly confounded researchers. Clinically, the side effects of tamoxifen can be very serious, ranging from liver steatosis to cirrhosis, tumorigenesis, or onset of porphyrias. Herein, we deciphered the nongenomic, mitochondrial cytotoxicity of tamoxifen in estrogen receptor positive MCF7 versus triple-negative MDA-MB-231 cells, employing the mitochondrial complex III quinoloxidizing-center inhibitor myxothiazol. We showed a role for hydroxyl-radical-mediated lipid peroxidation, catalyzed by iron, stemming from the redox interactions of tamoxifen quinoid metabolites with complex III, resulting in Fenton-capable reduced quinones. The role of tamoxifen semiquinone species in mitochondrial toxicity was also shown together with evidence of mitochondrial DNA damage. Tamoxifen caused an overall metabolic (respiratory and glycolytic) rate decrease in the Pasteur type MCF cells, while in the Warburg type MDA-MB-231 cells the respiratory rate was not significantly affected and the glycolytiv rate was significantly boosted. The nongenomic cytotoxicity of tamoxifens was hence associated with the metabolic phenotype and redox activity of the cells, as in the present paradigm of Pasteur MCF7s versus Warburg MDA-MB-231 cells. Our present findings call for caution in the use of the drugs, especially as a chemopreventive and/or in cases of iron overload diseases.

Photodynamic targeting of EGFR does not predict the treatment outcome in combination with the EGFR tyrosine kinase inhibitor Tyrphostin AG1478.

Photodynamic therapy (PDT) is a selective treatment modality against cancer. PDT is based on the preferential retention of photosensitizers (PSs), in the tumour and subsequent light exposure which activates the PS and generates reactive oxygen species. Multimodality therapy is increasingly relevant in cancer treatment and PDT has been shown as an effective adjuvant to other anti-cancer modalities. The present study reports on the combination of PDT and an epidermal growth factor receptor (EGFR) specific tyrosine kinase inhibitor (TKI), Tyrphostin AG1478. The combination was studied in two cell lines; A-431 and NuTu-19, expressing EGFR and sensitive to Tyrphostin treatment, but with different sensitivity towards photochemical EGFR damage. A-431 cells were treated with the PS meso-tetraphenylporphine with 2 sulfonate groups on adjacent phenyl rings (TPPS2a) in order to target mainly the endo/lysosomal compartments (18 h incubation followed by a 4 h chase in drug-free medium) or the plasma membrane (30 min incubation) upon light exposure. The EGFR was inhibited after PDT in A-431 cells only when TPPS2a was located on the plasma membrane, but both treatment regimes resulted in synergistic inhibition of cell growth when combined with Tyrphostin. TPPS2a treatment of NuTu-19 cells, designed for endo/lysosomal localization, followed by light attenuated EGFR phosphorylation but resulted in additive or antagonistic effects on cell growth when Tyrphostin was administered prior to or after PDT respectively. It was therefore concluded that photochemical damage of EGFR does not predict the treatment outcome when PDT is combined with Tyrphostin.