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305 Pharmacology > Cancer & Cell Cycle > Flashcards

Cancer & Cell Cycle Flashcards

1
Q

basis of signalling

A

first messengers (cytokines, growth factors, hormones, neurotransmitters, NO, histamines, eicosanoids, nucleotides) act on receiver cells, which synthesise secondary messengers (cyclic nucleotides & lipids)

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2
Q

cytokines

A

peptides/proteins derived from leukocytes that act to cause movement, growth or proliferation in cells by binding to cell surface receptos

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3
Q

dissociation constant

A

concentration at which 50% of receptors are occupied at equilibrium
Kd = koff/kon
ratio of dissociation rate and binding constant (specific to molecule and weight)

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4
Q

Ga size

A

39-46kDa; has major structural variation due to coding by ~20 genes

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5
Q

GTPase activity

A

a molecular clock, as conversion rate is known (kcat = 0.05sec^-1)
- can be increased by GAPs (GTPase activating proteins)

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6
Q

Gb size

A

37kDa

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7
Q

Gy size

A

8kDa

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8
Q

Receptor tyrosine kinase (RTK) mechanism

A

binding of ligand causes conformation change resulting in self-phosphorylation to create a binding site for SHC/Grb2/SOS. These activate Raf which activates MAPK phosphorylation cascade, resulting in phosphorylation of transcription factors to change gene expression

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9
Q

Ras GTPase superfamily

A

Can be activated by RTK, cytokine receptor, or the beta-gamma subunit of G proteins.
Causes MAPK phosphorylation cascade, which is facilitated by scaffold proteins.

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10
Q

MAPK pathway functions

A

mitosis, inflammatory response, differentiation, apoptosis

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11
Q

MAPK common activation loop

A

T-x-Y (Threonine - x - Tyrosine)
ERKs (TEY)
SAPKs (TPY)
p38 homologs (TGY)

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12
Q

Extracellular MAPK initiation

A

Ligand binding to RTK -> SHC/GRB2/SOS -> Ras GTP activation
-> Raf/MAPKKK -> MEK/MAPKK -> ERK -> MAPK ->
differentiation & cell division related genes

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13
Q

Stress MAPK initiation

A

Stress (UV/cytokine/heat) activate RasGTP -> MEK4 -> JNK/SAPs
= cell division stops, stress response

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14
Q

PAK

A

p21 activated kinase

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15
Q

SH2

A

domain that binds phospho-tyrosine
- present in STAT and also in Shc/Grb2/SOS complex

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16
Q

SH3

A

pro-line rich domain commonly found in cytoskeleton, allows localisation of proteins to membrane

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17
Q

paracrine

A

sender and receiver are in close proximity (tissue transmission)

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18
Q

juxtacrine

A

sender and receiver are next to each other (contact transmission)

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19
Q

autocrine

A

The same cell both secretes and receives the messenger (self transmission)

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20
Q

SHC

A

adaptor protein containing Sh2 sequence; binds to phospho-Tyr

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21
Q

Number of Tyrosine phosphorylated in RTKs

A

Tyr68

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22
Q

Grb2

A

growth factor receptor binding protein 2; an adaptor protein that binds to phosphorylated SHC protein via SH2 domain

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23
Q

p21Ras

A

subtypes of small monomeric GTP binding proteins.
Activated through guanine nucleotide exchange factor Sos and inactivated through GAP (GTPase activating protein).

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24
Q

Sos

A

son of sevenless; recruited to membrane by binding to SH3 domain of Grb2 to cause cause p21 Ras GTP exchange

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25
Q

Raf/MEKK/MAPKKK

A

ser/thr protein kinase activated by Ras-GTP and translocated to membrane. Alsoknown as MEKK or MAP kinase kinase kinase or MAP 3kinase (3 being number of downstream kinases)

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26
Q

MEK/MAPKK

A

dual specificity kinase activated by phosphorylation on 2 serine residues by Raf/MAPKKK/MEKK

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27
Q

ERK/MAPK/SAP

A

ser/thr kinase activated by phosphorylation on threonine and tyrosine residues by MEK and interacts with transcription factors to control gene expression

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28
Q

the cell cycle

A

controls growth, development, repair
heavily regulated by kinase activity and growth factors

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29
Q

cdks

A

cyclin-dependent kinases; activated by cyclins

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30
Q

g0

A

gap phase: cells are metabolically active but no growth occurs

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31
Q

G1

A

Growth of proteins and organelles necessary for growth processes and DNA replication processes.
Only phase that integrates external signals such as nutrients, growth factors, and suppressive factors with internal signalling.

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32
Q

G1 checkpoint

A

The restriction point assess whether there is sufficient nutrients and growth factors, it also checks DNA for any damage.

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33
Q

G1 regulation

A

Cyclin D
1. Links external and internal signals (Cyclin D generated by growth factor)
2. forms the cyclinD-cdk4/6 complex, allows cyclin E-cdk2 complex to form to drive through G1
3. Prepares for DNA replication through pocket proteins #RB protein activation

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34
Q

pocket proteins (RB)

A

RB, or retinoblastoma protein, acts to regulate whether gene transcription can occur.
- Couples cell cycle proteins #cyclin to the expression of genes required for cell cycle progression and DNA synthesis
- Also couples growth factors to gene expression
- mutations in RB account for 90% of Cancer

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35
Q

Pocket protein mechanism

A

Normally bind E2F, which prevents transcription. Phosphorylation by cdk4/6-cyclinD then cdk2-cyclin E allows E2F release, and gene expression of
- cyclin A & E
- DNA polymerase & helicase
- dihydrofolate reductases (purine synthesis)
- thyidilate synthase (pyrimidase)

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36
Q

Oncolytic adenovirus

A

Hijacking of adenovirus action: E1A frees Rb and E2F, driving into S phase, transcription of viral DNA = cell death and infection of nearby cells

removal of E1A gene means the virus can only act on cells with free E2F ie: will mainly target cancer cells with uncontrolled replication

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37
Q

S

A

DNA replication phase

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38
Q

G2

A

Growth of structures necessary for mitosis

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39
Q

G2 checkpoint

A

Checks that ‘S’ phase completed properly by sensing DNA damage and DNA replication integrity

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40
Q

G2 regulation

A

Nuclear envelope disintegration causes cyclin A degradation. Cyclin B synthesis rises until a threshold is reached.
Once sufficient cyclinB-cdk1 is reached, mitosis occurs
- Acts to condense DNA, disassemble nuclear envelope, rearrange cytoskeleton into spindles
- through phosphorylation of:
- Histones H1/H3 (to unwind DNA)
- Lamin (cytoskeleton)
- nucleolin (nucleus protein)

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41
Q

M

A

mitosis

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42
Q

M checkpoint

A

Senses spindle assembly, and that the chromosomes have separated correctly
Once chromosomes confirmed to be alg, cyclin B is degraded

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43
Q

M regulation

A

Controlled by cdk1 phosphorylation:
single phosphorylation by CAK/cdc25 = active, cells cannot exit from mitosis
triple phosphorylation (via Myt1/Wee1) = inactive = can exit from mitosis

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44
Q

regulation of Cdk

A

Temporally regulated by cyclin availability. Physically regulated by CKIs (cyclin-specific kinase inhibitors) and phosphorylation.

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45
Q

KIP/CIP

A

form complexes with cycling and cdks to prevent activation
= p21, p27, p57

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46
Q

INK4

A

binds cdk4/6
= p15, p16, p18, p19

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47
Q

cdk phosphorylation sites

A

threonine 14 & tyrosine 15 = inhibitory phosphorylation
threonine 160 = activating phosphorylation

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48
Q

p53

A

A transcription factor that detects damage in DNA. If damage is noticed, concentration of p53 increases and p21 is induced.

Expression of cdk is constitutive (always present), and increases in p53 are equally rapidly terminated

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49
Q

characteristics of cancer

A
  • sustained proliferative signalling
  • evading growth suppressors
  • tissue invasion and metastasis
  • replicative immortality
  • inducing angiogenesis
  • evading apoptosis
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50
Q

growth factors

A

act on RTKs to change gene transcription, typically result in cell cycle initiation

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51
Q

common mutations in cancer

A

kinases (autophosphorylation)
transcription factors
cyclin
p53
= continual cell cycle

52
Q

multi-step development

A

The idea that accumulation of mutations- caused by either toxins from environment, or by general errors in DNA replication- leads to increased liklihood of cancer development

Key event is a series of mutations that alter the cells ability to detect and repair damaged DNA.

= This allows the cells to survive and divide, causing a cascade of mutations that accumulate to become a malignant phenotype

53
Q

chemotherapy

A

often used as an adjunct therapy to surgery (tumour removal) and radiotherapy in order to reduce the chances of metastasis

often the only remaining treatment option once metastasis has occurred

used on a long term basis to reduce the chances of remission (re-occurrence of the cancer after a long period of time)

54
Q

log-kill hypothesis

A

based on the assumption that tumour size doubles every three months
- 2.5 years for a tumour to develop from 1g to 1kg resulting in death

cytotoxic drugs kill a certain percentage of cells (proportional to dose)
- tumour cells don’t rapidly recover, however healthy tissue does

55
Q

issues with chemotherapy treatment

A

even an extremely effective drug that kills 50% of a tumour will take two years to eradicate the tumour
- side effects on healthy cells can lead to death
- tumours can acquire drug resistance

56
Q

pulse therapy

A

administration of anti-cancer drugs with a rest phase to allow recover of healthy tissue
- minimise organ/immune damage and maintain tumour depletion

57
Q

combination therapy

A

administration of a drug ‘cocktail’ with different mechanisms of action and toxicities
- dispersal of side effects allows greater dose
- decreased chance of resistance
- synergistic effect

58
Q

cisplatin toxicity

A

renal

59
Q

bleomycin toxicity

A

pulmonary

60
Q

doxorubicin toxicity

A

cardiac

61
Q

vincristine/paciltaxel toxicity

A

neurological effects (impact microtubules)

62
Q

MTX/cyclophosphamide toxicity

A

immunosuppression

63
Q

drugs used to minimise side effects of chemo

A

anti-nausea, anti-emetics (anti-vom/nausea), analgesics, anti-wasting drugs

64
Q

alkylating agents

A

series of compounds based on sulphur gases that act to alkylate nitrogen atoms of guanine/nucleophilic centres in DNA to prevent or disrupt separation during replication
- single lesions (less effective, promote mutations)
- double lesions (link between/within strands to permanently distort DNA structure
abnormality (alkyl group) detected = apoptosis

65
Q

cyclophosphamide

A

an alkylating agent (targets DNA replication) that has good solubility, thus good action as a drug

66
Q

chlorambucil

A

an alkylating agent (targets DNA replication) that has a greater ability to pass through metabolism, that can be further distributed throughout the body

67
Q

nitrogen mustard

A

an alkylating agent (targets DNA replication) that causes inter-strand joining of DNA to cause apoptosis

68
Q

mitomycin C

A

an alkylating agent (targets DNA replication) that causes inter-strand joining of DNA to cause apoptosis

69
Q

cisplatin

A

an alkylating-like agent that distorts DNA causes cell death when DNA is separated for replication

70
Q

context of anti-folates

A

In order to form DNA, there must be sufficient nucleotides. Purines undergo synthesis through carbon addition via tetrahydrofolic acid (THFA)
- THFA is formed by reduction of folic acid, which is catalysed by dihydrofolate reductase
- Anti-folate drugs bind to inhibit dihydrofolate reductase

71
Q

MTX

A

an anti-folate (target purine synthesis);
a synthetic analogue of Folic acid that binds to dihydrofolate reductase with greater affinity than folic acid to inhibit it.

This limits formation of THFA, thus limiting nucleotide formation, thus DNA replication is arrested
+ Can also act as an immunosuppressant, as it acts on rapidly dividing cells such as white blood cells.
This decreases the speed of immune response, which is effective in conditions such as autoimmune disease

72
Q

anti-metabolites

A
  • Interfere with base precursors by acting as analogues of bases or base precursors
  • Act as pseudo feedback inhibitors
    1. In order to conserve energy, cells have feedback mechanisms to determine how many bases are present; and how many need to be synthesised. The analogues trick the cell into believing there are sufficient bases, and thus base synthesis is closed.
    2. Enzymes are unable to add natural bases to the synthetic ones, thus biosynthesis is blocked by the analogue
73
Q

6-fluorouracil

A

an anti-metabolite that acts to misleadingly convey negative feedback that sufficient endogenous bases are present, and blocks biosynthesis as cannot be incorporated into DNA

74
Q

anti-mitotic drugs

A

Interfere with microtubules requires for mitosis.
Can be used to synchronise cell replication by locking cells in mitotic phase, creating increase susceptibility of cells.

Cells populations are normally heterogenous; all cells are at different phases of cell cycle. This decreases the maximal of drugs that act in specific phases of the cell cycle. Anti-mitotic drugs drive cell populations to become homogenous.

(vinca alkaloids, taxanes)

75
Q

vinca alkaloids

A

anti-mitotic drugs that block microtubule assembly by inhibiting tubulin polymerisation, thus arrest mitosis at metaphase
Eg: vinblastine + vincristine

76
Q

vinblastine and vincristine

A

vinca alkaloids that block microtubule assembly by inhibiting tubulin polymerisation, thus arrest mitosis at metaphase

77
Q

taxanes

A

anti-mitotic drugs that block microtubules disassembly by binding preferentially to assembled tubulin to enhance the assembly of microtubules and stabilise them against depolymerisation

Mitosis is stopped when the stable, nonfunctional microtubules fail to form a normal mitotic apparatus

(eg: paciltaxel, docetaxel)

78
Q

actinomycin D

A

an antibiotic drug that inhibits the process of transcription in protein synthesis by binding to DNA (via three conjugated aromatic rings), preventing the movement of RNA polymerase (via chunky side chains)

79
Q

topoisomerase inhibitors

A

Bind to dsDNA and inhibit topoisomerase by stabilising the DNA complex, causing disrupting of replication

80
Q

topoisomerase

A

Topoisomerase is an enzyme that cuts (ssDNA or dsDNA) at ‘knots’ to relieve tension. Once ‘knot’ has been ligated must unravel.
Only ‘enzyme’ that does not chemically modify

Type I: Cuts one strand of DNA, increasing flexibility

Type II: cuts DNA through both strands
- disrupts ligation of dsDNA

81
Q

common side effects of chemotherapy

A
  • Alopecia (hair loss)
  • Gastrointestinal disorders (nausea, vomiting, anorexia, diarrhoea), and mucositis (inflammation of the mucous membranes of the GI tract and mouth) can be very severe and cause non-compliance
  • Fever, extravasation (dispersal of IV solution out of vessels and into tissues, causing necrosis), impaired immune function and wound healing
  • Long-term toxicity can include infertility and carcinogenic and teratogenic effects
82
Q

reasons why cell death is initiated

A
  • exposure to toxins, infection, injury, ischaemia, inflammation
  • maintain cell homeostasis
83
Q

extrinsic/death receptor apoptosis pathway

A
  • ligand (FasL/ TNF-a, TRAIL) binds to death receptor (Fas/TNFR1/DR5)
  • recruitment of death domains, which recruit adaptor proteins (DEDs)
  • DED binds pro-caspase 8
  • cleavage of pro-caspase 8 and dimerisation to form caspase 8
  • activation of caspase 3, 6, & 7 cause apoptosis by cleaving DNA and nuclear enzymes
84
Q

Death receptor ligands

A

FasL, TNF-a, TRAIL

85
Q

death receptors

A

Fas, TNFR1, DR5

86
Q

Pro-caspase 8

A

constitutively present in cytoplasm, implicated in extrinsic death pathway, requires cleavage and dimerisation to be activated

87
Q

action of caspase 8

A

activates caspase 3, 6 & 7 = cause cleavage of DNA and nuclear enzymes to cause apoptosis
+ truncates Bid -> tBid

88
Q

intrinsic/mitochondrial apoptotic pathway

A

pro-apoptotic Bcl proteins form transition pores in the mitochondria membrane
- Release of cytochrome C from inner membrane of mitochondria to cytoplasm
- formation of apoptosome by binding of Cyt. C and Apaf-1 x 7
- apoptosome binds caspase 9
- dimerisation of caspsae 9
- activation of other caspases, including caspase 3
- apoptosis

89
Q

apoptosome

A

formed from 7 units made up of cytochrome C and apaf-1 ATP-coupled binding

requirement for 7 subunits acts a threshold requiring sufficient damage to occur before apoptosis

90
Q

differentiating apoptosis vs necrosis

A

apoptosis requires ATP, necrosis does not.

Double staining with fluorescent Annexin-V and propidium iodide
= vertical; necrosis
= horizontal; apoptosis
(secondary necrosis always occurs in cell cultures due to limited ATP)

apoptosis plasma membrane remains intact, in necrosis it breaks apart

91
Q

Bcl-2 family

A

family of pro/anti-apoptotic molecules
- all contain a BH3 domain for ligand binding

92
Q

pro-apoptotic Bcl proteins

A

Bim, Puma, tBid, Bax, Bak, Noxa, Bad

93
Q

anti-apoptotic Bcl proteins

A

Bcl-2, Bcl-xL, Bcl-W, Mcl-1, A1

94
Q

shared features of extrinsic/intrinsic apoptosis

A
  • caspase 8 (from extrinsic) converts Bid to tBid (a pro-apoptotic Bcl) which stimulates Bax/Bak to form pores in mitochondria
  • both activate caspase 3
95
Q

apoptotic changes

A

DNA fragmentation, phosphatidylserine exposure, changes in cell shape, cell breaks apart & undergoes phagocytosis

96
Q

DIABLO-Smac

A

acts as a handbrake in intrinsic pathway: inhibits IAP, which inhibits caspase 3/9 (disinhibition)

97
Q

phosphatidylserine exposure

A

inversion of phospholipid of cell membrane causing membrane disintegration

98
Q

caspase enzymes

A

cysteine aspartate protease family that cleaves proteins after an aspartate residue
- secreted as zymogens/pro-enzymes thus are constitutively expressed and inactive
- cysteine site must be reduced for activation (caspases are inactive in highly oxidative environments)

99
Q

morphological changes in apoptosis

A
  • cell shrinkage
  • chromatin condensing
  • intact plasma membrane
  • formation of ‘blebs’ which package cellular contents into apoptotic bodies for phagocytosis
  • DNA fragmentation
  • nucleus forms pyknosis shape
100
Q

measurement of caspase activation

A

western blot

101
Q

measurement of mitochondrial changes

A
  • loss of outer membrane permeability = flow cytometry/TMRE (red mitochondrial stain)
  • release of proteins (cyt. C) = western blot comparing mitochondrial levels to cytosol
  • Bcl levels (western blot)
102
Q

measurement of DNA fragmentation

A
  • propidium iodide dye on fixed cells
  • flow cytometry
  • if peak below G2 (less than two chromosomes) indicates DNA fragmentation
103
Q

measurement of phosphatidylserine exposure

A
  • double staining with annexin-C and propidium iodide
  • flow cytometry
    = upwards movement = high PI, high A = necrosis
    = horizontal movement = low PI, high A = apoptosis
104
Q

non-classical apoptosis

A

Mechanisms of cell death that exist on the spectrum between classical apoptosis and necrosis.

Have similar processes, but with different involvement of certain enzymes, organelles, etc.. Eg: caspase-independent, lysosomal, autophagic

105
Q

necrosis

A

regulated by PARP & RIP1 kinase
- cell swells and bursts releasing intracellular contents including proteases and other damaging enzymes
- causes damage to surrounding tissue, thus provokes immune response
- cell debris often poorly cleared due to lack of scavenger receptors

106
Q

morphology of necrosis

A

(measure nucleus via Hoescht/DAPI or whole cell via electron microscopy)
- release of cellular contents
- DNA becomes diffuse
- cell swelling
- plasma membrane lysis

107
Q

biochemical detection of necrosis

A
  • low ATP
  • RIP1 kinase activation (western blot)
  • Trypan blue/techniques that show compromised membrane
  • annexin V + propidium iodide = high for both means necrosis
108
Q

NO synthesis

A

Arginine converted to hydroxy-arginine, converted to citrulline with NO as a biproduct
- mediated by H4B and CaM

109
Q

H4B

A

tetrahydrobiopterin

110
Q

Calmodulin

A

Binding of Ca2+ to calmodulin allows reductase and oxygenase domains of NOS to be in close proximity.
Allows electron flow (from NADPH) through flavin centres to Fe/H4B, which facilitates binding of oxygen to arginine

111
Q

NO diffusion time

A

0.001 second to cross cell membrane

112
Q

NOS-3

A

eNOS (133kDa)
constitutively active, calcium dependent, angiogenesis & smooth muscle relaxation

113
Q

NOS-2

A

iNOS (131kDa)
inducible, calcium independent, associated with immune defence via ONOO-

114
Q

NOS-1

A

nNOS (160kDa), constitutively active, calcium dependent, retrograde messenger

115
Q

NO downstream effects

A

binds to soluble guanylyl cyclase to increase cGMP, which phosphorylates PKG to promote the open state of cation channels

116
Q

eNOS mechanism

A

smooth muscle relaxation
- calmodulin (bound to Ca2+) activates myosin kinase, causing contraction
- NO binds to guanylyl cyclase, increasing cGMP
- cGMP activates PKG
- PKG pumps Ca2+ into intracellular domains, decreasing cGMP
= less Ca2+ = less calmodulin activation on myosin kinase + more phosphodiesterase = relaxation

117
Q

phosphodiesterase

A

dephosphorylates

118
Q

peroxynitrite (ONOO-)

A

synthesised when levels of NO are high
- DNA damage = p53 activation (apoptosis) & PARP activation
- mitochondrial damage = ATP depletion (due to damage and PARP activation) + calcium dyshomeostasis = necrosis

119
Q

NO as a retrograde messenger

A

NO (from nNOS) can diffuse to act on pre-synaptic terminal, enhancing glutamate release
and promoting dendritic growth by actions on guanylyl cyclase

120
Q

NO donors

A

used clinically for cardiovascular disease, pulmonary hypertension, topical wound healing
used experimentally for anti-inflammation, anti-cancer, anti-viral, and anti-bacterial action

121
Q

organonitrites

A

composed of ONO2 groups held together by alkyl group
used during cardiac surgery and in angina treatment

122
Q

GTN

A

nitroglycerin/glyceryl trinitrate
an organonitrite

123
Q

side effects of organonitrites

A

decreased blood pressure = headache

124
Q

NO as a cytotoxic drug

A

Nanoparticles are used to encapsulate NO donors.
includes polymeric carrier POEGMA-b-PPA to form protected NO donor (P-NO)
delivery micelle = P-NO-PMs

125
Q

mechanism of P-NO-PMs

A

nanoparticle encapsulate protected NO donors injected into blood, which travel to tumour via leaky blood vessels
- endocytosis into tumour cells
- nanoparticle degraded by acidic endosomes
- release of NO in presence of glutathione

126
Q

IAPs

A

inhibitor of apoptotic proteins

305 Pharmacology (4 decks)

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