Approaches for the integration of phytochemicals into classical cancer chemotherapy by modulation of multi-factorial drug resistance

Drug resistance has dogged oncology since decades. Overcoming drug resistance is urgently required to improve chemotherapy. The multiplicity of drug resistance implies that gene expression profiles predict drug resistance with higher accuracy than single gene expression studies. We analyzed different tumor types by microarray-based mRNA and immunohistochemistry-based protein analyses. Data were subjected to hierarchical cluster analyses. Expression profiles predicted drug response and survival times of patients. This may facilitate the development of individualized therapy options in the future. Strategies are to use either non-cross-resistant phytochemicals or natural products modulating resistance to standard anticancer drugs. We present three examples how natural products and their derivatives modulate resistance to established cancer drugs. (1) The anti-malarial artemisinin from Artemisia annua L. and its semi-synthetic derivatives inhibit the ATP-binding cassette (ABC) transporters P-glycoprotein/MDR1 and MRP1, which contribute to multidrug resistance phenotype of tumors and to the blood brain barrier. (2) Artesunate exerts synergistic activity in combination with Erlotinib, a small molecule tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) in transfected human glioblastoma multiforme cells. The inhibition of specific kinases in the EGFR downstream signaling pathways is responsible for this synergism. (3) Artesunate synergistically interacts with Rituximab, a monoclonal antibody against CD20 to treat Non-Hodgkin lymphoma. Rituximab affects the transcription factors NF-kappa B, Sp1, and YY1, which leads to altered expression profiles of anti-oxidant stress response or apoptosis-regulating genes, thereby increasing the activity of artesunate towards Non-Hodgkin lymphoma cells.