Browsing pathways

Thioguanine is a purine antimetabolite prodrug closely related to mercaptopurine and similarly inhibits purine metabolism. The thioguanine pathway is shown as a part of the mercaptopurine pathway. Thioguanine exerts cytotoxic effects via incorporation of thiodeoxyguanosine triphosphate into DNA and thioguanosine triphosphate into RNA and inhibition of Ras-related C3 botulinum toxin substrate 1, which induces apoptosis of activated T cells. Once in a cell, thioguanine is converted to thioguanosine monophosphate by hypoxanthine-guanine phosphoribosyltransferase. Thioguanosine monophosphate is then phosphorylated to thioguanosine diphosphate, which is converted via a thiodeoxyguanosine diphosphate intermediate to thiodeoxyguanosine triphosphate. Thiodeoxyguanosine triphosphate is incorporated into DNA causing cytotoxicity. Thioguanosine diphosphate is also converted to thioguanosine triphosphate which is incorporated into RNA. The thioguanosine triphosphate metabolite also inhibits Ras-related C3 botulinum toxin substrate 1, a plasma membrane-associated small GTPase that regulates cellular processes, inducing apoptosis in activated T cells.

Nicotine is a stimulant drug that acts as an agonist at nicotinic acetylcholine receptors. These are ionotropic receptors composed of five homomeric or heteromeric subunits. In the brain, nicotine binds to nicotinic acetylcholine receptors on dopaminergic neurons in the cortico-limbic pathways. This causes the channel to open and allow conductance of multiple cations including sodium, calcium, and potassium. This leads to depolarization, which activates voltage-gated calcium channels and allows more calcium to enter the axon terminal. Calcium stimulates vesicle trafficking towards the plasma membrane and the release of dopamine into the synapse. Dopamine binding to its receptors is responsible the euphoric and addictive properties of nicotine. Nicotine also binds to nicotinic acetylcholine receptors on the chromaffin cells in the adrenal medulla. Binding opens the ion channel allowing influx of sodium, causing depolarization of the cell, which activates voltage-gated calcium channels. Calcium triggers the release of epinephrine from intracellular vesicles into the bloodstream, which causes vasoconstriction, increased blood pressure, increased heart rate, and increased blood sugar.

Methotrexate is an antifolate antimetabolite used in the treatment of rheumatoid arthritis and cancer. Methotrexate is taken up into the cell by human reduced folate carriers (SLC19A1). In the cytoplasm, methotrexate is polyglutamated by folylpolyglutamate synthase, which enhances its retention inside the cell. Both methotrexate and methotrexate-polyglutamate inhibit dihydrofolate reductase, an enzyme that catalyzes the conversion of dihydrofolate into tetrahydrofolate, which is the active form of folic acid. Tetrahydrofolate is involved in many single-carbon transfer reactions, including the synthesis of DNA and RNA nucleotides. Inhibition of dihydrofolate reductase causes depletion of intracellular tetrahydrofolate, which has a cytotoxic effect, especially on rapidly dividing cells. Methotrexate-polyglutamate further inhibits de novo purine synthesis and thymidylate synthase, which contribute to methotrexate’s cytotoxic effects.

Irinotecan is a topoisomerase I inhibitor used in the treatment of cancer. It is hydrolyzed by esterases in the liver, intestine, and cytoplasm into the active metabolite SN-38, which binds to and inhibits the function of topoisomerase I. Topoisomerase I unwinds DNA by making transient single strand breaks that relieves the torsion of supercoiled DNA. In the unwound form, DNA can serve as a template for DNA replication as well as transcription. In the normal state, this effect is transient and the breaks DNA are quickly religated by topoisomerase I itself. SN-38 binding, however, inhibits religation and stabilizes the DNA-topoisomerase I complex in the cleaved DNA form, ultimately leading to breaks in both DNA chains and cell death.

Paclitaxel is an anticancer agent isolated from the bark of the yew tree. It is classified as a microtubule-stabilizing agent and exerts cell killing effects by disrupting mitosis in dividing cells. Microtubules are made up of α- and β- tubulin heterodimers arranged head to tail and assembled to form a cylinder. Microtubules possess complex polymerization dynamics that are essential for movement of chromosomes and proper segregation of daughter cells during mitosis. Paclitaxel binds directly to the inner surface of β-subunits along the length of microtubules. Binding is thought to induce a conformational change in tubulin that increases its affinity for neighbouring molecules. At sufficiently high concentrations, paclitaxel can bind to β-tubulin in a one to one ratio and stimulate microtubule polymerization. At lower clinically relevant drug concentrations, paclitaxel stabilizes microtubules and prohibits further polymerization and depolymerization. Suppression of microtubule dynamics may prevent chromosomes from moving from the spindle poles to the metaphase plate slowing or preventing progression from metaphase to anaphase. Cells enter a state of mitotic arrest from which they may progress to one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur causing cell death. Paclitaxel is susceptible to cellular drug resistance caused by drug efflux via a number of multidrug resistance-associated proteins.

Docetaxel, a semisynthetic analogue of paclitaxel, is an anticancer agent classified as a microtubule-stabilizing agent. Similar to paclitaxel, it exerts cell killing effects by disrupting mitosis in dividing cells. Microtubules are made up of α- and β- tubulin heterodimers arranged head to tail and assembled to form a cylinder. Microtubules possess complex polymerization dynamics that are essential for movement of chromosomes and proper segregation of daughter cells during mitosis. Docetaxel binds directly to the inner surface of β-subunits along the length of microtubules. Binding is thought to induce a conformational change in tubulin that increases its affinity for neighbouring molecules. At sufficiently high concentrations, docetaxel can bind to β-tubulin in a one to one ratio and stimulate microtubule polymerization. At lower clinically relevant drug concentrations, docetaxel stabilizes microtubules and prohibits further polymerization and depolymerization. Suppression of microtubule dynamics may prevent chromosomes from moving from the spindle poles to the metaphase plate slowing or preventing progression from metaphase to anaphase. Cells enter a state of mitotic arrest from which they may progress to one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur causing cell death. Docetaxel is susceptible to cellular drug resistance caused by drug efflux via a number of multidrug resistance-associated proteins.

Vinblastine, a vinca alkaloid isolated from the leaves of the periwinkle plant _Catharanthus roseus_, is an antimitotic anticancer agent. Its main mechanism of action is thought to be inhibition of microtubule dynamics, which results in mitotic arrest and eventual cell death. Vinblastine is a microtubule destabilizing agent. At high concentrations, it stimulates microtubule depolymerization and mitotic spindle destruction. At lower clinically relevant concentrations, vinblastine blocks mitotic progression. Its main targets are tubulin and microtubules. Unlike the taxanes, which bind poorly to soluble tubulin, vinblastine can bind both soluble and microtubule-associated tubulin. Rapid and reversible binding to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself. This is thought to play a key role in the kinetics of microtubule stabilization. Vinblastine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding of just one or two molecules of vinblastine greatly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the time microtubules spend in an attenuated state. This prevents proper assembly of the mitotic spindle and reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Vincristine, a vinca alkaloid isolated from the leaves of the periwinkle plant _Catharanthus roseus_, is an antimitotic anticancer agent. Its main mechanism of action is thought to be inhibition of microtubule dynamics, which results in mitotic arrest and eventual cell death. Vincristine is a microtubule destabilizing agent. At high concentrations, it stimulates microtubule depolymerization and mitotic spindle destruction. At lower clinically relevant concentrations, vincristine blocks mitotic progression. Its main targets are tubulin and microtubules. Unlike the taxanes, which bind poorly to soluble tubulin, vincristine can bind both soluble and microtubule-associated tubulin. Rapid and reversible binding to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself. This is thought to play a key role in the kinetics of microtubule stabilization. Vincristine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding of just one or two molecules of vincristine greatly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the time microtubules spend in an attenuated state. This prevents proper assembly of the mitotic spindle and reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Vindesine, a semisynthetic vinca alkaloid, is an antimitotic anticancer agent. Its main mechanism of action is thought to be inhibition of microtubule dynamics, which results in mitotic arrest and eventual cell death. Vindesine is a microtubule destabilizing agent. At high concentrations, it stimulates microtubule depolymerization and mitotic spindle destruction. At lower clinically relevant concentrations, vindesine blocks mitotic progression. Its main targets are tubulin and microtubules. Unlike the taxanes, which bind poorly to soluble tubulin, vindesine can bind both soluble and microtubule-associated tubulin. Rapid and reversible binding to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself. This is thought to play a key role in the kinetics of microtubule stabilization. Vindesine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding of just one or two molecules of vindesine greatly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the time microtubules spend in an attenuated state. This prevents proper assembly of the mitotic spindle and reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Vinorelbine, a semisynthetic vinca alkaloid, is an antimitotic anticancer agent. Its main mechanism of action is thought to be inhibition of microtubule dynamics, which results in mitotic arrest and eventual cell death. Vinorelbine is a microtubule destabilizing agent. At high concentrations, it stimulates microtubule depolymerization and mitotic spindle destruction. At lower clinically relevant concentrations, vinorelbine blocks mitotic progression. Its main targets are tubulin and microtubules. Unlike the taxanes, which bind poorly to soluble tubulin, vinorelbine can bind both soluble and microtubule-associated tubulin. Rapid and reversible binding to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself. This is thought to play a key role in the kinetics of microtubule stabilization. Vinorelbine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding of just one or two molecules of vinorelbine greatly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the time microtubules spend in an attenuated state. This prevents proper assembly of the mitotic spindle and reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.