Monofunctional platinum complexes restrain lung cancer through disrupting mitochondrial oxidative phosphorylation and glycolysis in addition to damaging nuclear and mitochondrial DNA.
Platinum(IV) complexes are prodrugs of cisplatin with multiple potential advantages over platinum(II) drugs. Mitochondria play pivotal roles in producing energy and inducing death of cancer cells. Two platinum(IV) complexes, namely, c,c,t-[Pt(NH)Cl(OH)(OCOCHCHCHCHPPh)]Br and c,c,t-[Pt(NH)Cl(OCOCHCHCHCHPPh)]Br, were designed to explore the effect of mitochondrion-targeting group(s) on the bioactivity and cytotoxicity of platinum(IV) complexes. The complexes were characterized by electrospray ionization mass spectrometry, reverse-phase high-performance liquid chromatography, and multinuclear (H, C,P, and Pt) NMR spectroscopy. The introduction of triphenylphosphonium targeting group(s) markedly influences the reactivity and cytotoxicity of the Pt(IV) complexes. The targeted complex displays more potent disruptive effect on mitochondria but less inhibitory effect on cancer cells than cisplatin. The lipophilicity of the Pt(IV) complexes is enhanced by the targeting group(s), while their reactivity to DNA is decreased. As a result, the mitochondrial morphology and adenosine triphosphate producing ability are impaired, which constitutes an alternative pathway to inhibit cancer cells. This study shows that both the reactivity of platinum(IV) center and the property of axial targeting ligand exert influences on the cytotoxicity of targeted Pt(IV) complexes. For targeting groups with pharmacological activities, their intrinsic function could enrich the anticancer mechanism of Pt(IV) complexes.
Theranostic agents are emerging multifunctional molecules capable of simultaneous therapy and diagnosis of diseases. We found that platinum(II)-gadolinium(III) complexes with the formula [{Pt(NH3)2Cl}2GdL](NO3)2 possess such properties. The Gd center is stable in solution and the cytoplasm, whereas the Pt centers undergo ligand substitution in cancer cells. The Pt units interact with DNA and significantly promote the cellular uptake of Gd complexes. The cytotoxicity of the Pt-Gd complexes is comparable to that of cisplatin at high concentrations (≥0.1 mM), and their proton relaxivity is higher than that of the commercial magnetic resonance imaging (MRI) contrast agent Gd-DTPA. T1-weighted MRI on B6 mice demonstrated that these complexes can reveal the accumulation of platinum drugs in vivo. Their cytotoxicity and imaging capabilities make the Pt-Gd complexes promising theranostic agents for cancer treatment.
Platinum(iv) prodrugs targeting the DNA repair mechanism downregulate myeloid cell leukemia-1 (Mcl-1) and homologous recombination proteins (RAD51, BRCA2), thereby enhancing cytotoxicity against cisplatin-resistant cancer cells.
Multidrug resistance (MDR) severely hinders the efficient chemotherapeutic treatments of cancer. d-α-Tocopherol polyethylene 1000 succinate (TPGS) based drug delivery system holds the potential of re-sensitizing resistant cancer cells. In this study, a TPGS prodrug containing both TPGS and mitoxantrone (MTO) via a disulphide bond was synthesised and assembled into micelle (TSMm) with a monodispersed diameter of 46.50 ± 1.12 nm. The disulphide bonds within the micelles could be cleaved in response to a high concentration of intracellular glutathione (GSH) after entering the tumour cells, leading a rapid release of MTO. In vitro cytotoxicity study showed TSMm significantly inhibited the growth of resistant breast tumour cells MDA-MB-231/MDR comparing to either free MTO or disulphide-free prodrug micelle (TCMm). In addition, TSMm could sustain favourable intracellular retention and cause the depletion of ATP activity, leading to the preferential transportation of MTO into the nucleus and the reversal of MDR. In vivo imaging also verified that TSMm was specifically targeted to the tumour regions at 24 h post injection. Finally, TSMm has significantly stronger antitumor activity in xenograft nude mice with negligible side effects. Hence, TSMm can serve as promising prodrug candidates to strengthen the reversal of MDR in tumours with less side effects.
Cancer
is characterized by abnormal cellular energy metabolism, which preferentially
switches to aerobic glycolysis rather than oxidative phosphorylation
as a means of glucose metabolism. Many key enzymes involved in the
abnormal glycolysis are potential targets of anticancer drugs. Platinum(IV)
complexes are potential anticancer prodrugs and kinetically more inert
than the platinum(II) counterparts, which offer an opportunity to
be modified by functional ligands for activation or targeted delivery.
A novel platinum(IV) complex, c,c,t-[Pt(NH3)2Cl2(C10H15N2O3S)(C2HO2Cl2)] (DPB), was designed to explore the
effects of axial ligands on the reactivity and bioactivity of the
complex as well as on tumor energy metabolism. The complex was characterized
by electrospray ionization mass spectrometry and multinuclear (1H, 13C, and 195Pt) NMR spectroscopy.
The introduction of dichloroacetate (DCA) markedly increases the lipophilicity,
reactivity, and cytotoxicity of the complex and blocks the growth
of cancer cells having active glycolysis, and the introduction of
biotin (C10H16N2O3S) enhances
the tumor-targeting potential of the complex. The cytotoxicity of
DPB is increased dramatically in a variety of cancer cell lines as
compared with the platinum(IV) complex PB without the DCA group. DPB
alters the mitochondrial membrane potential and disrupts the mitochondrial
morphology. The levels of mitochondrial and cellular reactive oxygen
species are also decreased. Furthermore, the mitochondrial function
of tumor cells was impaired by DPB, leading to the inhibition of both
glycolysis and glucose oxidation and finally to the death of cancer
cells via a mitochondria-mediated apoptotic pathway. These findings
demonstrate that DPB suppresses cancer cells mainly through altering
metabolic pathways and highlight the importance of dual-targeting
for the efficacy of anticancer drugs.
Fe3O4 nanoparticles with Pt-prodrug payloads display MRI capability and tumor-specific cytotoxicity correlating positively with glutathione-mediated DNA cleavage and reduction.
Mitochondrial
DNA (mtDNA) is an attractive cellular target for anticancer agents
in addition to nuclear DNA (nDNA). The cationic platinum(II) complex cis-[Pt(NP)(NH3)2Cl]NO3 (PtNP, NP = N-(2-ethylpyridine)-1,8-naphthalimide)
bearing the DNA-intercalating moiety NP was designed. The structure
of PtNP was fully characterized by single-crystal X-ray crystallography,
NMR, and HRMS. PtNP is superior to cisplatin in both in vitro and
in vivo anticancer activities with low systemic toxicity. The interaction
of PtNP with CT-DNA demonstrated that PtNP could effectively bind
to DNA through both covalent and noncovalent double binding modes.
In addition to causing significant damage to nDNA and remarkable inhibition
to DNA damage repair, PtNP also distributed in mitochondria, inducing
mtDNA damage and affecting the downstream transcriptional level of
mitochondrion-encoded genes. In addition, PtNP disturbed the physiological
processes of mitochondria by reducing the mitochondrial membrane potential
and promoting the generation of reactive oxygen species. Mechanistic
studies demonstrate that PtNP induced apoptosis via mitochondrial
pathways by upregulating Bax and Puma and downregulating Bcl-2 proteins,
leading to the release of cytochrome c and activation
of caspase-3 and caspase-9. As a dual-DNA-damage agent, PtNP is able
to improve the anticancer activity by damaging both nuclear and mitochondrial
DNA, thus providing a new anticancer mechanism of action for the naphthalimide
monofunctional platinum(II) complexes.
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