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Novel mechanisms of action of putative pro-apoptotic BH3 mimetics and their potential therapeutic use / by Ryan Scot Soderquist.

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Author	Soderquist, Ryan Scot.
Title	Novel mechanisms of action of putative pro-apoptotic BH3 mimetics and their potential therapeutic use / by Ryan Scot Soderquist.
Date	2014
Abstract	The BCL2 family of proteins control intrinsic apoptosis at the mitochondria through a delicate balance of pro and anti-apoptotic proteins. Anti-apoptotic proteins are frequently relied upon by cancer cells, making them ideal targets for chemotherapy. BH3 mimetics are small molecules that mimic the function of pro-apoptotic BH3-only proteins by binding and inhibiting anti-apoptotic proteins. ABT-737 is a BH3 mimetic that inhibits BCL2 and BCLXL, whereas ABT-199 inhibits only BCL2. While these BCL2 inhibitors have demonstrated efficacy at killing cancer cells, resistance is frequently observed due to reliance on additional anti-apoptotic proteins (e.g., MCL1 and BFL1), highlighting the need for inhibitors of these proteins. We compared many novel putative BH3 mimetics for their mechanism of action in cells and found that most do not function as BH3 mimetics in cells, rather they activate the integrated stress response and induce NOXA, a BH3-only protein that inhibits MCL1 and BFL1. These putative BH3 mimetics sensitize leukemia cells to ABT-737 and ABT-199. With three of these compounds (S1, gossypol and MIM1), we confirmed that this sensittization is NOXA-dependent. Importantly, gossypol and S1 resensitize chronic lymphocytic leukemia (CLL) cells to ABT-737 and ABT-199 in a model of resistance to these BCL2 inhibitors. We further characterized the mechanisms of NOXA induction for S1, gossypol and MIM1. Surprisingly, these compounds induced different cellular stresses, ultimately converging on induction of the integrated stress response and NOXA. S1 activates this pathway by increasing reactive oxygen species, whereas gossypol does so by activating phospholipase A2, which leads to an increase in cytoplasmic calcium. How MIM1 activates the ISR is unknown, but is different from either S1 or gossypol; nor does it induce NOXA by inhibiting the proteasome. Lastly, we demonstrated that gossypol can completely resensitize CLL cells to BCL2 inhibitors in a stroma-CLL co-culture system, which justifies a combined clinical trial with ABT-199 and AT-101 (a racemer of gossypol). In addition, the failure of many BH3 mimetics to inhibit their putative targets in cells highlights many pitfalls to avoid when developing novel anticancer drugs.
Description	xv, 131 leaves : ill.
Format	application/pdf
College	Dartmouth Medical School. Department of Pharmacology and Toxicology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1245

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