Abstract
Cisplatin is the first and most widely used platinum-based chemotherapy drug and is the cornerstone agent in treating a broad spectrum of cancers. However, its clinical application is often limited by severe toxic side effects and drug resistance. Based on the discovered dissociative electron transfer mechanism of cisplatin, a novel combination of cisplatin with [9-(2-carboxyphenyl)-6-diethylamino-3-xanthenylidene]-diethylammonium chloride (basic violet 10, BV10) is proposed to potentiate the chemotherapeutic effect of cisplatin. Here, we show that this combination enhances the anti-cancer effect of cisplatin in both in vitro cell lines and in vivo xenograft mouse models of cisplatin-sensitive and -resistant lung, ovarian and cervical cancers while introducing minimal additional toxic side effects. Furthermore, femtosecond time-resolved laser spectroscopic measurements demonstrate that cisplatin reacts with BV10 via an electron transfer mechanism. These results indicate that the combination of cisplatin with BV10 is promising for improving the chemotherapy of cancers with various extents of cisplatin resistance.
Highlights
Cisplatin is the first and most widely used platinum-based chemotherapy drug and is the cornerstone agent in treating a broad spectrum of cancers
This study demonstrates that the dissociative electron transfer (DET)-based combination regimen of CDDP can effectively enhance the anticancer activity of CDDP for the treatment of various cancers with various degree of CDDP resistance
Our in vivo xenograft mouse models show that the anti-tumor effect of CDDP was significantly enhanced with the combination with BV10, in contrast to the combination of cisplatin with TMPD that showed effective in vitro but no in vivo[27]
Summary
Cisplatin is the first and most widely used platinum-based chemotherapy drug and is the cornerstone agent in treating a broad spectrum of cancers. Femtosecond time-resolved laser spectroscopic measurements demonstrate that cisplatin reacts with BV10 via an electron transfer mechanism These results indicate that the combination of cisplatin with BV10 is promising for improving the chemotherapy of cancers with various extents of cisplatin resistance. Its dose-dependent toxicities include nephrotoxicity and neurotoxicity[6,7], mainly due to the binding of the heavy-metal platinum (Pt) to proteins in kidneys[8,9] These problems are so severe that they even prompted the call to discontinue the clinical use of Pt-based anticancer drugs[10]. Based on the hydrolysis mechanism, many studies have aimed to circumvent the drawbacks of CDDP over the past 50 years; over 3000 CDDP analogues have been designed, synthesized and tested, but only two have been approved by the FDA to treat certain types of cancer: oxaliplatin and carboplatin. Using fs-TRLS, Lu et al.[20] have unraveled the molecular mechanism for enhancing the therapeutic efficacy of radiotherapy by low-dose CDDP, and found that it is due to the extremely effective dissociative electron transfer (DET) reaction of CDDP with the weakly-bound prehydrated electron ( ep−re ) generated by radiolysis of water: e−pre + Pt(NH3)2Cl2 → [Pt(NH3)2Cl2]∗− → Pt(NH3)2Cl + Cl−
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