Design of new anticancer drugs by selectable intracellular organelle targeting: make for the mitochondria or turn left for the lysosome?

Mincher, D.; Kamel, M.; Mohammed, O.; MacCallum, J.; Turnbull, A.

Abstract

Introduction
Defining structural features that can control and pinpoint the delivery of drugs to specific sub-cellular organelles ofcancer cells offers the prospect of designing more potentand selective drugs that negate drug resistance, with less detrimental side-effects for the patient. Several vectors, including cationic peptides, are known to transport drug cargo efficiently to mitochondria. Utilizing a disubstituted anthraquinone template, this study combines the vector triphenylphosphonium (TPP) and the mitochondrial-active dichloroacetic acid (DCA) synergistically to achieve selective targeting of cancer cell mitochondria, by exploiting mitochondrial membrane potential differences.
Material and Methods
A library of novel spacer-linked, anthraquinone-TPP-DCA-conjugates (code-named MK) was synthesized and characterized. The anti proliferative activity ofcompounds were determined in a panel of cancer cell lines including PC3 prostate adenocarcinoma, MCF7 breast carcinoma, and HCT-15 colon carcinoma cell lines. Morphological changes, cell-based assays of induction of apoptosis and sub-cellular localisation ofcompounds defined by confocal microscopy were performed.
Results and Discussions
Notably, the conjugates were equally potent at low or submicromolar concentrations in cell lines with low (MCF7),moderate (PC3) and high (HCT-15) levels of P-gpexpression, suggesting circumvention of P-gp mediated drug efflux. In HCT-15, two lead conjugates (MK39 andMK44) had IC50 values of 3.2 µM ± 0.09 and 3.7 ± 0.02µM respectively, induced cell shrinkage, nuclearcontraction and plasma membrane blebbing (1 µM at 4h);whereas mitoxantrone (1 µM at 4h) had no effect. MK39 and MK44 localized exclusively in mitochondria and did not enter the nucleus, with the prospect of averting genotoxicity. Significantly, by addition of a polyaminespacer group between the anthraquinone and the TPP vector, we demonstrated that agents can be ‘diverted’exclusively to lysosomes.
Conclusion
Novel compounds have been designed that can be targeted exclusively to cancer cell mitochondria. Furthermore, pharmacophores have been identified for insertion into a single scaffold to re-route the compounds to the lysosomes. The ability to exert control over sub-cellular destinations and trigger apoptosis has potential for new anticancer drug development.

Citation

Mincher, D., Kamel, M., Mohammed, O., MacCallum, J., & Turnbull, A. (2024, June). Design of new anticancer drugs by selectable intracellular organelle targeting: make for the mitochondria or turn left for the lysosome?. Presented at EACR 2024: Innovative Cancer Science, Rotterdam, Netherlands

• Presentation Conference Type: Conference Abstract
• Conference Name: EACR 2024: Innovative Cancer Science
• Start Date: Jun 10, 2024
• End Date: Jun 13, 2024
• Acceptance Date: Dec 1, 2024
• Online Publication Date: Jun 6, 2024
• Publication Date: 2024-06
• Deposit Date: Jun 19, 2024
• Publicly Available Date: Jun 19, 2024
• Journal: Molecular Oncology
• Print ISSN: 1574-7891
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 18
• Issue: S1
• Pages: 290
• DOI: https://doi.org/10.1002/1878-0261.13683
• Additional Information: Published: 2024-06-06