| Title: |
Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift |
| Authors: |
Tantawy, Mohammed N.; McIntyre, J. Oliver; Yull, Fiona; Calcutt, M. Wade; Koktysh, Dmitry S.; Wilson, Andrew J.; Zu, Zhongliang; Nyman, Jeff; Rhoades, Julie; Peterson, Todd E.; Colvin, Daniel; McCawley, Lisa J.; Rook, Jerri. M.; Fingleton, Barbara; Crispens, Marta Ann; Alvarez, Ronald D.; Gore, John C. |
| Contributors: |
National Institutes of Health; U.S. Department of Defense; Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center |
| Source: |
Cancer Medicine ; volume 13, issue 3 ; ISSN 2045-7634 2045-7634 |
| Publisher Information: |
Wiley |
| Publication Year: |
2024 |
| Collection: |
Wiley Online Library (Open Access Articles via Crossref) |
| Description: |
Background It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth. Additionally, acidosis in the TME has been reported to play a key role in selecting for a more aggressive tumor phenotype, drug resistance and desensitization to immunotherapy for many types of cancers. TME‐HAP is an attractive target for tumor detection and treatment development since HAP is generally absent from normal soft tissue. We provide strong evidence that dissolution of hydroxyapatite (HAP) within the tumor microenvironment (TME‐HAP) using a novel therapeutic can be used to kill cancer cells both in vitro and in vivo with minimal adverse effects. Methods We developed an injectable cation exchange nano particulate sulfonated polystyrene solution (NSPS) that we engineered to dissolve TME‐HAP, inducing localized acute alkalosis and inhibition of tumor growth and glucose metabolism. This was evaluated in cell culture using 4T1, MDA‐MB‐231 triple negative breast cancer cells, MCF10 normal breast cells, and H292 lung cancer cells, and in vivo using orthotopic mouse models of cancer that contained detectable microenvironment HAP including breast (MMTV‐Neu, 4T1, and MDA‐MB‐231), prostate (PC3) and colon (HCA7) cancer using 18 F‐NaF for HAP and 18 F‐FDG for glucose metabolism with PET imaging. On the other hand, H292 lung tumor cells that lacked detectable microenvironment HAP and MCF10a normal breast cells that do not produce HAP served as negative controls. Tumor microenvironment pH levels following injection of NSPS were evaluated via Chemical Exchange Saturation (CEST) MRI and via ex vivo methods. Results Within 24 h of adding the small concentration of 1X of NSPS (~7 μM), we observed significant tumor cell death (~ 10%, p < 0.05) in 4T1 and MDA‐MB‐231 cell cultures that contain HAP but ⟨2% in H292 and MCF10a cells that lack detectable HAP and in controls. Using CEST MRI, we found extracellular pH (pHe) in the 4T1 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1002/cam4.6812 |
| Availability: |
https://doi.org/10.1002/cam4.6812; https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.6812 |
| Rights: |
http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.E0210C5D |
| Database: |
BASE |