Cancer Biochemistry PDF

Target tumor metabolism: Achilles’ heel Lower doses to minimize side effects **New Drug Strategies**...

Target tumor metabolism: Achilles’ heel Lower doses to minimize side effects **New Drug Strategies** Enhance specificity for tumor cells Efflux Pumps: P-glycoprotein expels drugs Mechanisms Microenvironmental Factors: Tumor pH and hypoxia reduce drug efficacy **Multidrug Resistance (MDR)** Common in domestic pets (dogs, cats) Pre-treatment with metabolic inhibitors **Epidemiology** Solutions Influenced by lifestyle factors, genetic predispositions, and differing exposures to environmental carcinogens Polypharmacological therapy Genetic heritage Develop therapies that specifically target tumor vulnerabilities (e.g., metabolism, angiogenesis) **Goals** **Multifactorial Disease** Lifestyle: diet, habits Reduce side effects and resistance through multimodal approaches Environmental factors: occupational, social, **Treatment** **Causes of Cancer** cultural Antiglycolytic agents: 3-BP, 2-DG, DCA **Emerging Approaches** Internal: immune response, genetic predispositions Combination therapies to counter resistance **Internal vs External Causes** External: 80–90% related to environment Screening: Detect early-stage cancers (e.g., PSA for prostate cancer) Fatty foods: red meats, fried foods Diagnosis and Prognosis: Confirm cancer types and predict outcomes. Nitrites: processed meats (pickles, sausages) **Dietary** Treatment Monitoring: Track response and Smoked/barbecued foods: tar from coal smoke detect relapses High-temperature cooking α-Fetoprotein: Elevated in liver cancer. Solar radiation → skin cancers Carcinoembryonic Antigen (CEA): Monitors colon and pancreatic cancer Examples: **Tumor Markers** Chemicals → carcinogens (benzaldehyde) PSA: Prostate-specific antigen for prostate cancer **Risk Factors** **Environmental** Viruses: HPV → cervical cancer Sustained Proliferative Signaling: Tumors continuously signal cells to divide Bacteria: H. pylori → gastric cancer Evading Apoptosis: Cancer cells resist programmed cell death Radiation: UV and ionizing radiation cause direct DNA damage, leading to mutations Angiogenesis: They induce blood vessel formation. Key Hallmarks (Hanahan and Weinberg, 2011): **Hormonal** Sterilization reduces breast tumor risk in pets Metabolic Reprogramming: Tumors increase glucose uptake and modify nutrient usage to fuel rapid growth Certain dog breeds have higher risks: Golden **Genetic Predispositions** Retrievers, Boxers Tumors prefer glycolysis for ATP production, producing large amounts of lactate, even in aerobic conditions Metabolic Reprogramming: Tumors prioritize glycolysis (Warburg effect), Increased glycolysis meets anabolic needs for rapid proliferation. even in oxygen-rich conditions Cancer Biochemistry Benign: Benign tumors are non-invasive and localized, posing minimal risk unless their growth interferes with vital functions Mind Map **Benign vs Malignant Tumors** Malignant: invasive, metastatic Weight loss, muscle wasting, anemia **Symptoms** Loss of cell adhesion (E-cadherin): They Insulin resistance, high cortisol, lipolysis, evade neighboring tissues proteolysis Invasive capability: They cross barriers, aided **Malignancy Mechanisms** Tumors outcompete normal tissues for glucose by enzymes like collagenase and nutrients **Cancer Development** Metastasis: They spread through blood and Increased proteolysis and lipolysis lead to lymphatic systems to colonize distant organs muscle wasting and fat loss **Mechanisms** **Cachexia in Cancer** Initiation: Genetic mutations occur due to Elevated cortisol and pro-inflammatory carcinogens (DNA damage) cytokines drive metabolic disruption Promotion: Mutated cells proliferate under "oncopromoters," **Stages of Carcinogenesis** Low-carbohydrate diets or metabolic modulators may a process that may halt if exposure ceases help reduce tumor resource access Progression: Uncontrolled cell division becomes irreversible, solidifying cancer and metastasis High glycolytic rates result in excessive lactate production. Checkpoint Regulation: It halts the cell cycle at the G1/S transition if Reduced mitochondrial activity exacerbates DNA damage is detected, allowing repair mechanisms to act lactate buildup Lactic Acidosis in Cancer **p53 – Guardian of the Genome** Apoptosis Induction: If DNA damage is irreparable, p53 initiates programmed Implications include systemic acidosis and cell death (apoptosis) to prevent the survival of defective cells nutrient deficiencies **Genetics in Cancer** Proto-oncogenes: Normal genes regulating growth and division. When Example: RAS, which controls cell signaling, mutated, they become oncogenes, driving malignancy often mutates to promote uncontrolled division HIF1 Activation: Stimulates glycolytic enzymes **Oncogenes vs Tumor Suppressor Genes** and VEGF expression for angiogenesis Tumor Suppressor Genes: Prevent tumor formation by regulating the cell cycle TP53 (p53), RB1 (retinoblastoma protein) Effects of Hypoxia: or apoptosis. Mutations lead to a loss of this protective function Metabolic Adaptation: Enhances tumor survival in oxygen-poor environments. **Hypoxia and Angiogenesis** Types of Mutations: Include point mutations, deletions, and Tumors release VEGF, binding to endothelial cell chromosomal translocations. These can activate oncogenes receptors. or disable tumor suppressor genes Angiogenesis Process: Mechanisms of Mutation: Endothelial cells proliferate and migrate toward Early mutations in APC (a tumor suppressor gene) the tumor, forming new blood vessels Sequence of Events: For instance, in colon cancer: Later mutations in KRAS (oncogene) and p53, resulting in progression to malignancy Plasma membrane fluidity increases, enabling migration. **Mutations and Cancer** Structural Changes: Structural Changes: Cancer cells have increased plasma membrane fluidity and less organized Loss of cytoskeletal organization gives cells a rounded shape. cytoskeletons, making them more invasive Cancer cells proliferate uncontrollably and evade apoptosis. Functional Changes: They lose specialized Functional Changes: Tumor Cell Changes Consequences of Mutations: functions and become "immortal," dividing They induce angiogenesis (new blood vessel formation) to indefinitely sustain growth Metabolic Changes: Tumor cells consume more Increased glucose uptake and metabolic activity energy, altering host metabolism. Metabolic Changes: **Metabolism in Tumor Cells** Metabolic shifts benefit tumor survival but strain the host Tumors compress nearby tissues, impairing their Local Effects: function Biochemical markers, such as elevated liver Tumor Characteristics enzymes or LDH, indicate systemic changes Systemic Effects: Tumors often hijack nutrients, disrupting normal metabolism