HIF pharmacological manipulation

Question 1

In recent years, researchers have begun to explore..

Answer 1

pharmacological manipulation of the HIF pathway in search of therapeutic benefit

Question 2

PHD enzymes involved in hydroxylation of HIF1a

Answer 2

facilitate degradation of HIF1a in normoxic conditions, proposed as drug targets

Question 3

Inhibition of PHD activity prevents HIF degradation

Answer 3

leading to HIF accumulation and transcriptional activation of target genes

Question 4

Roxadustat

Answer 4

drug used in treatment of anemia
associated with chronic kidney disease
stimulate erythropoeisis

Question 5

Roxadustat findings

Answer 5

Shown to increase mean Hb concentration in CKD patients not undergoing dialysis (Chen, 2019)

Question 6

Effect of roxadustat (PHD inhibitor) in long term dialysis patients

Answer 6

Effect not as pronounced but non-inferior to parenteral epoetin alfa as therapy for anemia in chinese CKD patients undergoing dialysis (Chen, 2019)

Question 7

However, HIF activation can be used for therapeutic benefit…

Answer 7

potential misuse of drugs like Roxadustat in sport for performance enhancement is considered doping

Question 8

Athletes may be attracted to substances that enhance O2 carrying capacity of blood

Answer 8

increased RBC production can potentially improve endurance and overall athletic performance

Question 9

PHD inhbiitor and therefore HIF activator dimethyloxalylglycine (DMOG)

Answer 9

has previously been shown as protective in murine models of colitis (Cummins, 2008)

Question 10

While these effects proved reproducible leading to development of clinical trials

Answer 10

results from phase II proved discouraging demonstrating no clear evidence of therapeutic benefit

Question 11

HIF dysregulation and activation in cancer

Answer 11

contributes to tumour growth, angiogenesis and survival

Question 12

In recent years much effort poured into developing innovative cancer treatments that target HIF pathway

Answer 12

Combining HIF inhibitors with current cancer therapys such as chemo to increase anti-tumour activity and diminish treatment resistance is a strategy for combating therapeutic resistance

Question 13

Infusion of PHD inhibitors promising in ischaemic conditions (reduced blood flow and oxygen supply to tissues)

Answer 13

PHI (PHD inhibitor) administration stabilises HIF promoting an adaptive adaptive glycolytic response that aids cellular survival under low oxygen conditions

Question 14

Degree and duration of hypoxia experienced during ischaemia

Answer 14

significantly influences potential for recovery

Question 15

Ongoing clinical trials investigating use of PHIs to limit ischaemic events with aim of

Answer 15

enhancing recovery by promoting cellular adaptations to hypoxia

Question 16

by mitigating the consequences of O2 deprivation

Answer 16

PHIs present as an innovative approach to minimise ischamic injury and imporve patient outcome in aftermath of stroke and heart attack

Question 17

Metformin diabetes drug

Answer 17

Shown to inhibit tumour growth and downregulate HIF1a and VEGF expression in gallbladder cancer (Ye et al, 2018)

Question 18

Wound healing

Answer 18

Angiogenesis and tissue repair
Accelerate wound healing
HIF modulation in chronic wound healing