Photodamaging of Mitochondrial DNA to Overcome Cisplatin Resistance by a Ru^II–Pt^II Bimetallic Complex

Abstract

Emerging studies have shown that mitochondrial DNA (mtDNA) is an attractive target for anticancer therapeutics. Herein, a heterobimetallic complex [Ru(dip)2(μ‐bpm)PtCl2]Cl2 (RuPt; dip=4,7‐diphenyl‐1,10‐phenanthroline; bpm=2,2′‐bipyrimidine) and the corresponding mononuclear complex [Ru(dip)2(bpm)]Cl2 (Ru) have been designed and synthesized. RuPt can bind to mtDNA and damage it both in the dark and upon visible light irradiation. By using a variety of methods, it was demonstrated that RuPt can interfere with the function of mtDNA by decreasing the amplification and copy number of mtDNA, and affecting the transcriptional level of mitochondria‐encoded genes. Furthermore, RuPt can disturb the physiological processes of mitochondria and induce caspase‐dependent apoptosis in the presence of light. In addition, RuPt shows low systemic toxicity and potent in vivo anticancer potency upon light irradiation. This study provides strong evidence that mtDNA is an important molecular target of RuPt, and photodamaging mtDNA is an effective strategy to overcome cisplatin resistance.

Redirecting Cisplatin and Doxorubicin to Mitochondria Affords Highly Effective PlatinumIV Prodrug Against Triple Negative Breast Cancer

“…Damage to mtDNA was further confirmed using confocal microscopy by employing DNA intercalating fluorophore PicoGreen that can label the mtDNA. As shown in Figure 4, treatment with PPD triggers nuclear remodelling which is evident with the formation of giant and bright nucleotide, which is considered to be a sign of mtDNA damage [22] …”

Light‐Triggered Nitric Oxide Release by a Photosensitizer to Combat Bacterial Biofilm Infections

“…These complexes display typical metal‐to‐ligand charge‐transfer (MLCT) absorption bands at 350–550 nm (Figure S1 in the Supporting Information). The single oxygen quantum yields of Ru II compounds ( Φ Δ ) upon excitation at 425 nm were determined using 9,10‐anthracenediyl‐bis(methylene)dimalonic acid in aqueous solution (Figure S2) [24] . The relative Φ Δ values of RNO , RB , and RBNO were calculated to be 0.23, 0.20, and 0.22, respectively (Figure 1 b).…”

“…The single oxygen quantum yields of Ru II compounds (F D )u pon excitation at 425 nm were determined using 9,10-anthracenediyl-bis(methylene)dimalonic acid in aqueous solution ( Figure S2). [24] The relative F D values of RNO, RB,a nd RBNO were calculated to be 0.23, 0.20, and 0.22, respectively ( Figure 1b).…”

DNA interaction, photocleavage and theoretical calculations of a ruthenium(II) complex with hydroxyquinoline derivative

“…If both strands are cleaved, a linear form (Form III) is generated that migrates between Form I and II. 43 As seen in Fig. 8, lane 1 is the pure DNA alone and lane 2 is the DNA with 24 μM of complex present in the dark, both of which resulted in little or no DNA cleavage.…”