Abstract
Resistance towards chemotherapeutics displayed by cancer cells is a significant stumbling block against fruitful cisplatin-based therapy. A unique dual-acting chemotherapeutic modality, Platin-B, a prodrug of cisplatin and pipobroman-mimicking alkylating agent, was constructed to circumvent tumor resistance. Platin-B exhibited a superior cytotoxicity profile in cisplatin-resistant cancer cells. Enhanced activity and the ability to overcome cancer-induced resistance of Platin-B was related to adduct formation with intracellular glutathione, followed by the activity of Platin-B on the mitochondria of cells, along with its conventional nuclear activity. Alkylating moieties present on Platin-B enhanced its cellular and subcellular concentration and protected it from early drug sequestration by biological thiols. A unique dual-acting chemotherapeutic modality Platin-B, a prodrug of PtIV and pipobroman-mimicking alkylating agent, was constructed to act on the mitochondria of cells by using its pendent -Br moieties to induce changes in mitochondrial bioenergetics, formation of repair-inactive Pt-DNA adducts, and ultimately participation in mitochondrial apoptosis and loss of mitochondrial mass to overcome resistance compared to other similar Pt-based compounds.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3029-3036 |
| Number of pages | 8 |
| Journal | Chemistry - A European Journal |
| Volume | 22 |
| Issue number | 9 |
| DOIs | |
| State | Published - Feb 24 2016 |
| Externally published | Yes |
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Keywords
- alkylating agent
- cancer
- cisplatin
- DNA repair
- glutathione
ASJC Scopus subject areas
- Chemistry(all)
Cite this
Unique Use of Alkylation for Chemo-Redox Activity by a PtIV Prodrug. / Pathak, Rakesh K.; Dhar, Shanta.
In: Chemistry - A European Journal, Vol. 22, No. 9, 24.02.2016, p. 3029-3036.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Unique Use of Alkylation for Chemo-Redox Activity by a PtIV Prodrug
AU - Pathak, Rakesh K.
AU - Dhar, Shanta
PY - 2016/2/24
Y1 - 2016/2/24
N2 - Resistance towards chemotherapeutics displayed by cancer cells is a significant stumbling block against fruitful cisplatin-based therapy. A unique dual-acting chemotherapeutic modality, Platin-B, a prodrug of cisplatin and pipobroman-mimicking alkylating agent, was constructed to circumvent tumor resistance. Platin-B exhibited a superior cytotoxicity profile in cisplatin-resistant cancer cells. Enhanced activity and the ability to overcome cancer-induced resistance of Platin-B was related to adduct formation with intracellular glutathione, followed by the activity of Platin-B on the mitochondria of cells, along with its conventional nuclear activity. Alkylating moieties present on Platin-B enhanced its cellular and subcellular concentration and protected it from early drug sequestration by biological thiols. A unique dual-acting chemotherapeutic modality Platin-B, a prodrug of PtIV and pipobroman-mimicking alkylating agent, was constructed to act on the mitochondria of cells by using its pendent -Br moieties to induce changes in mitochondrial bioenergetics, formation of repair-inactive Pt-DNA adducts, and ultimately participation in mitochondrial apoptosis and loss of mitochondrial mass to overcome resistance compared to other similar Pt-based compounds.
AB - Resistance towards chemotherapeutics displayed by cancer cells is a significant stumbling block against fruitful cisplatin-based therapy. A unique dual-acting chemotherapeutic modality, Platin-B, a prodrug of cisplatin and pipobroman-mimicking alkylating agent, was constructed to circumvent tumor resistance. Platin-B exhibited a superior cytotoxicity profile in cisplatin-resistant cancer cells. Enhanced activity and the ability to overcome cancer-induced resistance of Platin-B was related to adduct formation with intracellular glutathione, followed by the activity of Platin-B on the mitochondria of cells, along with its conventional nuclear activity. Alkylating moieties present on Platin-B enhanced its cellular and subcellular concentration and protected it from early drug sequestration by biological thiols. A unique dual-acting chemotherapeutic modality Platin-B, a prodrug of PtIV and pipobroman-mimicking alkylating agent, was constructed to act on the mitochondria of cells by using its pendent -Br moieties to induce changes in mitochondrial bioenergetics, formation of repair-inactive Pt-DNA adducts, and ultimately participation in mitochondrial apoptosis and loss of mitochondrial mass to overcome resistance compared to other similar Pt-based compounds.
KW - alkylating agent
KW - cancer
KW - cisplatin
KW - DNA repair
KW - glutathione
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UR - http://www.scopus.com/inward/citedby.url?scp=84962600931&partnerID=8YFLogxK
U2 - 10.1002/chem.201503866
DO - 10.1002/chem.201503866
M3 - Article
C2 - 25043175
AN - SCOPUS:84962600931
VL - 22
SP - 3029
EP - 3036
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
SN - 0947-6539
IS - 9
ER -