PHAR 3505 Prof Chaudhuri

2. Describe the multiple effects guggulsterone may have on cancer cells

In some cancers, there is an over-activation of the Cdk4 receptors, through the over-production of cyclin D1.  

Over-active Cdk4 receptors are also responsible for the over-activation of the other Cdk receptors (Cdk2 and Cdk1).

These receptors are responsible for mediating the different stages of the cell within the cycle; (Cdk4 = for G0/G1 phase, Cdk2 = for G1/S phase and Cdk1 = for G2/M phase).  
Guggulsterone is a natural product which:
1) decreases the levels of cyclin D1, preventing formation of active Cdk4, thus vblocking G0/G1 phase of cancer cell.

2) Increases  levels of p21 and p27, which inhibit Cdk4 and Cdk2 = inhibiton of Go/G1 phase, and G1/S phase of cancer cell.
3) Inhibits DNA polymerase, acting on the S phase of the cell cycle.

In breast cancer, there is an increase in production of Estradiol (AKA Oestrogen), this leads to an increase in Oestrogen receptor activity, and essentially increases the amount of cell division- without any cell apoptosis (tumor growth).

Estradiol is created from testosterone by the enzyme Aromatase (AKA Cyp19).

The FXR receptor has the job of regulating the Cyp19 enzyme, and inhibiting it when necessary.

In Breast cancer- the FXR is faulty, this allowing the CyP19 to overproduce Estradiol etc. (as above).

Thus in order to increase the activity of FXR, we require an FXR agonist. And so guggulsterone is known to be an agonist of FXR receptor in high concentration, in Breast cells. This can cause cancer cell apoptosis.

(NOTE: Guggulsterone is also an antagonist of FXR for Cyp7a in Cholesterol) 

3. What is the role of Cdks in the cell division cycle and how would you use natural product derivatives to control dividing cells which have become immortal?

An activated Cdk (cyclin dependent kinase) contains:

·         Catalytic subunit –responsible for the catalysis of the phosphorylation reaction on Ser/Thr amino acid residues.

·         Regulatory subunit known as cyclin – Positive regulators of the Cdk activity i.e in order for the phosphorylation of the Ser/Thr amino acids to occur the regulatory subunit must bind to the catalytic subunit.

Cdks power the cell cycle- needed for normal cell division in cancer activated partner not degraded and constantly produced thereby keeping the Cdk active all the time. The inactivating tumour suppressor protein partner loses inactivating ability through mutation in their corresponding genes and therefore is unable to negatively regulate Cdk activity (not able to downregulate)

Anticancer compounds target Cdk:

A)     Inhibition of Cdk catalytic subunit (small molecular weight inhibitor that fits into the active site of Cdk)

B)      Degradation/downregulating the over produced cyclin which has already made the Cdk over-active.

C)      Reinducing levels of tumour suppressor proteins.

Natural product- Flavopiridol and P276 (Flavonoids) inhibit:

1.       Cdk4 by blocking the cells at G0/G1 phase

2.       Cdk2 by blocking the cells at G1/S phase

3.       Cdk1 by blocking the cells at G2/M phase

All three Cdks constantly active…