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Multimodal Approach to Tumor Therapy with Quercetin, Chemotherapy, Radiotherapy and Hyperthermia

Quercetin is the major representative of the flavonoid subclass of flavonols. Due to its anti-oxidant, anti-tumor and anti-inflammatory activity, quercetin has been studied extensively as a chemopreventive agent in several cancer models. Quercetin has been shown to inhibit proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. In addition, our studies and those by others showed that quercetin could „sensitize“ cancer cells to chemotherapeutic agents, likely by blocking NF-kappaB activation induced by chemotherapeutic agents both in vitro and in vivo. Furthermore, pretreatment with quercetin sensitizes cancer cells to growth inhibition and apoptosis induced by chemotherapeutic agents. By inhibiting P-glycoprotein 1 (P-gp) activity, quercetin also increases the accumulation of chemotherapeutics in P-gp expressing cancer cells which results in altered absorption/bioavailability of these drugs after coadministration with quercetin. These results provide experimental evidence that novel therapeutic strategies for human cancer could be developed to achieve better treatment outcome by introducing flavonoid quercetin in the therapeutic regimen. In an effort to improve local tumor control, a multimodality treatment strategy including regional hyperthermia (RHT), chemotherapy and immunomodulation with quercetin, seems to be very attractive in the treatment of various tumors. The rationale for the combination of cytotoxic drugs with hyperthermia in the treatment of tumor is based on experimental evidence that heat exposure increases the killing of tumor cells by direct thermal cytotoxicity and is able to sensitize perfused tumor tissue towards chemotherapy in a synergistic manner. Hyperthermia combined with conventional chemotherapy has meanwhile been integrated in multimodality treatment strategies for various tumors. Hyperthermia is a promising approach for cancer therapy because it not only kills cancer cells directly, but also activates anti-cancer immunity as an indirect effect. In addition, hyperthermia enhances the clastogenicity of alkylating agents. The objective of our study was to see whether pretreatment with quercetin could enhance the cytotoxic and apoptotic effect of commonly used chemotherapeutic agents or radiation for the treatment of different tumors. In addition, we determined whether quercetin has the potential to serve as a beneficial supplement before hyperthermal intraperitoneal chemotherapy (HIPEC) and whether quercetin can reduce clastogenic effect of cisplatin, irinotecan and other chemoterapeutics on healthy tissue in mice bearing tumor. These aspects of quercetin are discussed further in detail in this review.

quercetin ; tumor ; hyperthermia ; chemotherapy ; radiotherapy

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