The novel capsazepine analog, CIDD ‐99, significantly inhibits oral squamous cell carcinoma in vivo through a TRPV 1‐independent induction of ER stress, mitochondrial dysfunction, and apoptosis
Background Oral squamous cell carcinoma ( OSCC ) is a deadly disease with a mere 40% five‐year survival rate for patients with advanced disease. Previously, we discovered that capsazepine ( CPZ ), a transient receptor potential channel, Vanilloid subtype 1 ( TRPV 1) antagonist, has significant anti‐...
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Published in | Journal of oral pathology & medicine Vol. 48; no. 5; pp. 389 - 399 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
01.05.2019
|
Online Access | Get full text |
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Summary: | Background
Oral squamous cell carcinoma (
OSCC
) is a deadly disease with a mere 40% five‐year survival rate for patients with advanced disease. Previously, we discovered that capsazepine (
CPZ
), a transient receptor potential channel, Vanilloid subtype 1 (
TRPV
1) antagonist, has significant anti‐tumor effects against
OSCC
via a unique mechanism‐of‐action that is independent of
TRPV
1. Thus, we developed novel
CPZ
analogs with more potent anti‐proliferative effects (
CIDD
‐24,
CIDD
‐99, and
CIDD
‐111).
Methods
Using
OSCC
xenograft models, we determined the efficacy of these analogs in vivo.
TRPV
1 interactions were evaluated using calcium imaging and a rat model of orofacial pain. Anti‐cancer mechanism(s)‐of‐action were assessed by cell cycle analysis and mitochondrial depolarization assays.
Results
CIDD
‐99 was the most potent analog demonstrating significant anti‐tumor effects in vivo (
P
< 0.001).
CIDD
‐24 was equipotent to the parent compound
CPZ
, but less potent than
CIDD
‐99.
CIDD
‐111 was the least efficacious analog. Calcium imaging studies confirmed that
CIDD
‐99 neither activates nor inhibits
TRPV
1 confirming that
TRPV
1 activity is not involved in its anti‐cancer effects. All analogs induced an S‐phase block, dose‐dependent mitochondrial depolarization, and apoptosis. Histological analyses revealed increased apoptosis and reduced cell proliferation in tumors treated with these analogs. Importantly,
CIDD
‐99 had the most dramatic anti‐tumor effects with 85% of tumors resolving leaving only minute traces of viable tissue. Additionally,
CIDD
‐99 was non‐noxious and demonstrated no observable adverse reactions
Conclusion
This study describes a novel, highly efficacious,
CPZ
analog,
CIDD
‐99, with dramatic anti‐tumor effects against
OSCC
that may be efficacious as a lone therapy or in combination with standard therapies. |
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ISSN: | 0904-2512 1600-0714 |
DOI: | 10.1111/jop.12843 |