Abstract
Detailed understanding of metabolic reprogramming in cancer cells and associated crosstalk with the redox circuitry is indispensable for the development of effective therapeutic modalities to treat cancer. An increase in aerobic glycolysis, pentose phosphate pathway, serine glycine one carbon metabolism with a concomitant decrease in oxidative phosphorylation are the fundamental metabolic pathways modulated in cancer cells during the malignant transformation and metastasis. The metabolic reprogramming impacts functioning of intracellular organelles like mitochondria and endoplasmic reticulum resulting in electron escape and production of free electron radicals like O2−, H2O2, and OH.. While ROS inactivates tumor suppressor PTEN, mitogen-activated protein kinase phosphatase, c-Jun N-terminal and p38 pro-death pathways, it activates ERK, PI3K/Akt signaling, HIF-1α, NF-kB, and Nrf2 pro-survival signaling pathways that are responsible for upregulation of antioxidant genes and proteins including antioxidant factors (GSH and NADPH), thereby accentuating the proliferation and aggressiveness of tumors. These principal alterations provide a selective advantage to cancer cells by modulating the bioenergetics, biosynthesis, and redox status thereby leading to cancer cell survival, proliferation, and tumorigenesis. A wide variety of modifiers of metabolic oxidative stress inhibits the energy production in cancer cells and also enhances the intracellular ROS pool through the blockage of antioxidant molecules and redox cofactors production. Polypharmacological agents like 2-deoxy-D-glucose, operates through multiple mechanisms involving glycolysis inhibition, oxidative stress, unfolded protein response, and immunomodulation, consequently inducing cancer cell death and achieving therapeutic gain. The chapter reviews the conceptual framework of metabolic oxidative stress and molecular cues that orchestrates the process of malignant transformation and metastasis, besides their role in resistance to therapy. We also present here the potential metabolic pathway modifiers that are currently in their preclinical and clinical stages of development with a focus on potential metabolic targets linked to enhanced oxidative stress.
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Bera, S., Verma, A., Bhatt, A.N., Dwarakanath, B.S. (2022). Metabolic Oxidative Stress in Initiation, Progression, and Therapy of Cancer. In: Chakraborti, S., Ray, B.K., Roychoudhury, S. (eds) Handbook of Oxidative Stress in Cancer: Mechanistic Aspects. Springer, Singapore. https://doi.org/10.1007/978-981-15-9411-3_138
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