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Characterization of a New Anti-Cancer Compound Using Multi-Cellular Tumour Spheroids


Characterization of a New Anti-Cancer Compound Using Multi-Cellular Tumour Spheroids

Larocque, Kevin (2018) Characterization of a New Anti-Cancer Compound Using Multi-Cellular Tumour Spheroids. Masters thesis, Concordia University.

Text (application/pdf)
Larocque_MSc_F2018.pdf - Accepted Version


We synthesized a thieonoisoquinoline scaffold amenable to modifications and found that several derivatives selectively kill cancer cells in the nanomolar range. Further characterization of one of these molecules, C75, revealed that it uniquely targets spindle poles. This phenotype is due to specific functional groups and not the scaffold because another derivative, C87, has no effect on cells. To demonstrate C75’s potential for use in vivo, we found that C75 successfully regresses or inhibits the growth of multi-cellular tumour spheroids grown from HeLa (cervical cancer), A549 (lung cancer) and HCT-116 (colorectal cancer) cells. Since C75 is a small molecule, we also determined if controlling its delivery and release would improve its efficacy in spheroids. As a proof-of-concept, we tested the release of Doxorubicin (Dox) from novel polymer-based nanoparticles with dual-controlled release in HeLa and A549 spheroids. Dox levels from nanoparticles increased sooner, and to a greater extent within the core of spheroids vs. free Dox. Encapsulating C75 in similar nanoparticles increased its efficacy in HeLa and A549 spheroids compared to free compound. Lastly, we also explored the potential to use C75 in combination therapies with paclitaxel (TaxolTM), which is an anti-cancer drug that patients often develop resistance to and/or causes severe side-effects. We found that C75 and paclitaxel have different mechanisms of action at a cellular level, and cause regression of HCT 116 spheroids when used in combination at subthreshold doses. Thus, our results show that C75 has the potential to be explored for its use as an anti-cancer drug.

Divisions:Concordia University > Faculty of Arts and Science > Biology
Item Type:Thesis (Masters)
Authors:Larocque, Kevin
Institution:Concordia University
Degree Name:M. Sc.
Date:1 August 2018
Thesis Supervisor(s):Piekny, Alisa
ID Code:984319
Deposited On:16 Nov 2018 16:31
Last Modified:16 Nov 2018 16:31
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