4 research outputs found
Hypoxia-Directed and Self-Immolative Theranostic Agent: Imaging and Treatment of Cancer and Bacterial Infections
The impact of bacteria on cancer progression and treatment
is becoming
increasingly recognized. Cancer-associated bacteria are linked to
metastases, reduced efficacy, and survival challenges. In this study,
we present a sensitive hypoxia-activated prodrug, NR-NO2, which comprises an antibiotic combined
with a chemotherapeutic. This prodrug demonstrates rapid and robust
fluorescence enhancement and exhibits potent antibacterial activity
against both Gram-positive and Gram-negative bacteria as well as tumor
cells. Upon activation, NR-NO2 produces a distinct “fluorescence-on” signal, enabling
real-time drug release monitoring. By leveraging elevated nitroreductase
in cancer cells, NR-NO2 gives
rise to heightened bacterial cytotoxicity while sparing normal cells.
In A549 solid tumor-bearing mice, NR-NO2 selectively accumulated at tumor sites, displaying fluorescence
signals under hypoxia superior to those of a corresponding prodrug-like
control. These findings highlight the potential of NR-NO2 as a promising cancer therapy prodrug that
benefits from targeted release, antibacterial impact, and imaging-based
guidance
Hypoxia-Directed and Self-Immolative Theranostic Agent: Imaging and Treatment of Cancer and Bacterial Infections
The impact of bacteria on cancer progression and treatment
is becoming
increasingly recognized. Cancer-associated bacteria are linked to
metastases, reduced efficacy, and survival challenges. In this study,
we present a sensitive hypoxia-activated prodrug, NR-NO2, which comprises an antibiotic combined
with a chemotherapeutic. This prodrug demonstrates rapid and robust
fluorescence enhancement and exhibits potent antibacterial activity
against both Gram-positive and Gram-negative bacteria as well as tumor
cells. Upon activation, NR-NO2 produces a distinct “fluorescence-on” signal, enabling
real-time drug release monitoring. By leveraging elevated nitroreductase
in cancer cells, NR-NO2 gives
rise to heightened bacterial cytotoxicity while sparing normal cells.
In A549 solid tumor-bearing mice, NR-NO2 selectively accumulated at tumor sites, displaying fluorescence
signals under hypoxia superior to those of a corresponding prodrug-like
control. These findings highlight the potential of NR-NO2 as a promising cancer therapy prodrug that
benefits from targeted release, antibacterial impact, and imaging-based
guidance
An Activatable Prodrug for the Treatment of Metastatic Tumors
Metastatic
cancers have historically been difficult to treat. However, metastatic
tumors have been found to have high levels of reactive oxygen species
such as hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), supporting
the hypothesis that a prodrug could be activated by intracellular
H<sub>2</sub>O<sub>2</sub> and lead to a potential antimetastatic
therapy. In this study, prodrug <b>7</b> was designed to be
activated by H<sub>2</sub>O<sub>2</sub>-mediated boronate oxidation,
resulting in activation of the fluorophore for detection and release
of the therapeutic agent, SN-38. Drug release from prodrug <b>7</b> was investigated by monitoring fluorescence after addition of H<sub>2</sub>O<sub>2</sub> to the cancer cells. Prodrug <b>7</b> activated
by H<sub>2</sub>O<sub>2,</sub> selectively inhibited tumor cell growth.
Furthermore, intratracheally administered prodrug <b>7</b> showed
effective antitumor activity in a mouse model of metastatic lung disease.
Thus, this H<sub>2</sub>O<sub>2</sub>-responsive prodrug has therapeutic
potential as a novel treatment for metastatic cancer via cellular
imaging with fluorescence as well as selective release of the anticancer
drug, SN-38
GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy
<p>Recent progress in chemotherapy has significantly increased its efficacy, yet the development of chemoresistance remains a major drawback. In this study, we show that GFRA1/GFRα1 (GDNF family receptor α 1), contributes to cisplatin-induced chemoresistance by regulating autophagy in osteosarcoma. We demonstrate that cisplatin treatment induced GFRA1 expression in human osteosarcoma cells. Induction of GFRA1 expression reduced cisplatin-induced apoptotic cell death and it significantly increased osteosarcoma cell survival via autophagy. GFRA1 regulates AMPK-dependent autophagy by promoting SRC phosphorylation independent of proto-oncogene <i>RET</i> kinase. Cisplatin-resistant osteosarcoma cells showed NFKB1/NFκB-mediated GFRA1 expression. GFRA1 expression promoted tumor formation and growth in mouse xenograft models and inhibition of autophagy in a GFRA1-expressing xenograft mouse model during cisplatin treatment effectively reduced tumor growth and increased survival. In cisplatin-treated patients, treatment period and metastatic status were associated with GFRA1-mediated autophagy. These findings suggest that GFRA1-mediated autophagy is a promising novel target for overcoming cisplatin resistance in osteosarcoma.</p