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Complexation of cisplatin with a p53 activator as a single anticancer agent resulted in synergistically improved cytotoxicity in p53 wild-type but not p53 null human cancer cells. Mechanistic investigation was carried out on this dual-targeting Pt(IV) prodrug, chalcoplatin. The prodrug effectively entered cancer cells and arrested the cell cycle at...
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The use of platinum-based chemotherapeutic drugs in cancer therapy still suffers from severe disadvantages, such as lack of appropriate selectivity for tumor tissues and insurgence of multi-drug resistance. Moreover, drug efficacy can be attenuated by several mechanisms such as premature drug inactivation, reduced drug uptake inside cells and incre...
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... Zhu et al. proposed an elegant approach based on the chemical conjugation of cisplatin and chalcone, which was reported to act as an inhibitor of p53-MDM2 interactions [147]. The resulting Pt(IV) prodrug 37 was shown to release both components upon reduction in the cancer cell milieu. ...
... In contrast, the cytotoxicity of 37 was comparable to cisplatin in 53-null cancer cells. In agreement with the design, complex 37 demonstrated a dramatic increase of p53 expression in comparison with cisplatin [147]. ...
... induction of p53-dependent apoptosis (reduced when treated with p53 inhibitor pifithrin-α) [116] 31 increase of p53 protein expression [119] 32 higher activity in cancer cells with wild-type p53 status abrogated activity in HCT116 cells with p53 mutations decrease of p73 expression activation of p21 in vitro activity was dependent on p21 expression and independent of p73 expression [126] 33 activation of p53 and p21 expression and p53 phosphorylation reduced p53 and p21 expression in cells treated with p53 inhibitor pifithrin-α cytotoxicity was not significantly affected by pifithrin-α [127] 34 increase of p53 and phospho-p53(Ser15) protein levels decreased p21 expression [128] cisplatin in general, resistance to cisplatin is linked to p53 mutations and the loss of wild-type p53 function sensitivity of cancer cells to cisplatin was not only dictated by p53 status/function, but also other factors [137][138][139][140][142][143][144][145][146] induction of p53-dependent apoptosis (reduced when treated with p53 inhibitor pifithrin-α) [116] 31 oxaliplatin in general, more active in cell lines with a wild-type p53 status than in cell lines with a mutated p53 status might be more active in cell lines with a mutated p53 status and less active in cell lines with wildtype p53 -p53-dependent and p53-independent mechanisms [133,141] 37 the cytotoxicity was higher than for cisplatin in cells with wildtype p53 status dose-dependent increase of p53 expression [147] 38 increase of p53, p71, p21 expression in SK-OV-3/DDP cells decrease in apoptosis in p53-siRNA SK-OV-3/DDP cells [148] 39 increase of phospho-p53(Ser15) levels in U87 cells [149] 40 increase of p53 expression in HT- ...
Simple Summary
It is believed that metal complexes might be interesting alternatives to the small organic molecules for the treatment of cancer. Due to the variety of metal oxidation states and geometries, the structure of metal complexes can be easily modified based on the required design. For example, metal complexes can be specifically designed to interact with the p53 protein or its binding partners. The aim of this article is to discuss whether metal complexes can have a future as p53-targeting drugs.
Abstract
P53 plays a key role in protecting the human genome from DNA-related mutations; however, it is one of the most frequently mutated genes in cancer. The P53 family members p63 and p73 were also shown to play important roles in cancer development and progression. Currently, there are various organic molecules from different structural classes of compounds that could reactivate the function of wild-type p53, degrade or inhibit mutant p53, etc. It was shown that: (1) the function of the wild-type p53 protein was dependent on the presence of Zn atoms, and (2) Zn supplementation restored the altered conformation of the mutant p53 protein. This prompted us to question whether the dependence of p53 on Zn and other metals might be used as a cancer vulnerability. This review article focuses on the role of different metals in the structure and function of p53, as well as discusses the effects of metal complexes based on Zn, Cu, Fe, Ru, Au, Ag, Pd, Pt, Ir, V, Mo, Bi and Sn on the p53 protein and p53-associated signaling.
... [11] Moreover, bioactive axial ligands such as enzyme inhibitors, small molecule drugs, peptides, and targeting moieties have been utilized to achieve multifunctionalization and multitargeting. [12] Examples of axial ligands include glutathione S-transferase inhibitors, [13] cyclooxygenase inhibitors, [14] histone deacetylase inhibitors, [15] p53 activators, [16] PARPi, [17] receptor-targeting groups, [18] mitochondria-targeting groups, [19] DNA alkylating agents, [20] and many other organic drugs and bioactive molecules. [21] Many multitargeted Pt IV prodrugs have displayed excellent antitumor activities both in vitro and in vivo. ...
Although multitargeted PtIV anticancer prodrugs have shown significant activities in reducing drug resistance, the types of bioactive ligands and drugs that can be conjugated to the Pt center remain limited to O‐donors. Herein, we report the synthesis of PtIV complexes bearing axial pyridines via ligand exchange reactions. Unexpectedly, the axial pyridines are quickly released after reduction, indicating their potential to be utilized as axial leaving groups. We further expand our synthetic approach to obtaining two multitargeted PtIV prodrugs containing bioactive pyridinyl ligands: a PARP inhibitor and an EGFR tyrosine kinase inhibitor; these conjugates exhibit great potential for overcoming drug resistance, and the latter conjugate inhibits the growth of Pt‐resistant tumor in vivo. This research adds to the array of synthetic methods for accessing PtIV prodrugs and significantly increases the types of bioactive axial ligands that can be conjugated to a PtIV center.
... t, J = 7.4 Hz, 2H, triaz-CH 2 ), 2.55 (t, J = 7.4 Hz, 2H, CH 2 CO).13 C NMR (125 MHz, D 2 O) δ 180.90 (CO), 147.92 (triaz-C), 122.15 (triaz-CH), 87.35 (C-1), 78.79 (C-5), 75.87 (C-3), 72.22 (C-2), 68.92 (C-4), 60.40 (C-6), 36.18 (CH 2 CO), 21.49 (triaz-CH 2). ...
Despite the enormous importance of cisplatin as a chemotherapeutic agent, its application is impacted by dose-limiting side effects and lack of selectivity for cancer cells. Researchers can overcome these issues by taking advantage of the pro-drug nature of the platinum(IV) oxidation state, and by modifying the coordination sphere of the metal centre with specific vectors whose receptors are overexpressed in tumour cell membranes (e.g., carbohydrates). In this paper we report the synthesis of four novel carbohydrate-modified Pt(IV) pro-drugs, based on the cisplatin scaffold, and their biological activity against osteosarcoma (OS), a malignant tumour which is most common in adolescents and young adults. The carbohydrate-targeting vectors and Pt scaffold are linked using copper-catalysed azide–alkyne cycloaddition (CuAAC) chemistry, which is synonymous with mild and robust reaction conditions. The novel complexes are characterised using multinuclear 1D-2D NMR (1H, 13C and 195Pt), IR, HR-MS, Elem. Analyses, and CV. Cytotoxicity on 2D and 3D and cell morphology studies on OS cell lines, as well as non-cancerous human foetal osteoblasts (hFOBs), are discussed.
... Interestingly enough, this outstanding activity was related to efcient (but undefned) transport-mediated cellular uptake, as well as an "instant" reductive activation process. Furthermore, in monochalcoplatin, the presence of the two equatorial chlorido ligands appears to be essential for its striking uptake since the oxaliplatin-based Pt(IV) analogue appears to be deprived of any transport mechanism [22,23]. ...
The biological behavior of the axially unsymmetric antitumor prodrug (OC-6-44)-acetatodiamminedichloridohydroxidoplatinum(IV), 2, was deeply investigated and compared with that of analogous symmetric Pt(IV) complexes, namely, dihydroxido 1 and diacetato 3, which have a similar structure. The complexes were tested on a panel of human tumor cell lines. Complex 2 showed an anomalous higher cytotoxicity (similar to that of cisplatin) with respect to their analogues 1 and 3. Their reduction potentials, reduction kinetics, lipophilicity, and membrane affinity are compared. Cellular uptake and DNA platination of Pt(IV) complexes were deeply investigated in the sensitive A2780 human ovarian cancer cell line and in the corresponding resistant A2780cisR subline. The unexpected activity of 2 appears to be related to its peculiar cellular accumulation and not to a different rate of reduction or a different efficacy in DNA platination and/or efficiency in apoptosis induction. Although the exact mechanism of cell uptake is not fully deciphered, a series of naïve experiments indicates an energy-dependent, carrier-mediated transport: the organic cation transporters (OCTs) are the likely proteins involved.
... [43][44][45] However, other studies showed that the tendency of platinum accumulation cannot be exclusively attributed to the changes in lipophilicity. [46][47][48] Although we cannot rule out the possibility that berplatin can increase its cell uptake in the form of active transport or increased lipophilicity, our data clearly show that the endocytosis pathway plays a key role in berplatins' cell uptake, and this pathway provides a way to circumvent cisplatin resistance. Interestingly, the uptake of berplatin in normal cells is not dependent on active endocytosis. ...
Design of Pt(IV) prodrugs with biologically active axial ligands is an excellent approach to overcome the disadvantages (nonspecific killing, side effects, and drug resistance) of conventional first‐line Pt(II)‐based chemotherapeutic drugs, such as cisplatin, carboplatin and oxaliplatin. The selection of ideal axial ligands is essential for the success of Pt(IV) drugs. Previously, that berberine exhibits great superiority in tumor selectivity is found with uncovered mechanisms. In this study, that berberine is specifically internalized and accumulated in tumors but not normal cells through endocytosis pathways is first disclosed. Therefore a new Pt(IV) prodrug of cisplatin bearing berberine as an axial ligand, named berplatin, is designed and synthesized. Different from cisplatin, berplatin can be effectively and selectively internalized into cancer cells, through macropinocytosis and caveolin‐1 (CAV‐1)‐dependent active endocytosis, and cleaved in intracellular reductive environments to generate cisplatin and berberine, which synergistically induces substantial DNA breaking, apoptosis and cell cycle arrest in both cisplatin‐sensitive and ‐resistant cancer cells. In vivo, berplatin manifests much higher antitumor activity and undetectable side effects compared to cisplatin. This study demonstrates that berplatin can serve as a potent Pt(IV) prodrug for the treatment of cisplatin‐sensitive and ‐resistant cancers with active uptake, excellent specificity, and minimal side effects.
... Further studies on neurotoxicology and biodistribution should be pursued to understand the effects of higher platinum concentrations reaching healthy brain tissue. In this regard, alternative development of targeted conjugates and drug combination strategies, by conjugating axially two or four (in case of oxaliplatin) anti-cancer bioactive ligands such as p53 reactivators [77,78], should also be considered to maximize platinum efficacy and minimize off-site toxicity [79]. ...
Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, with a median survival of approximately 15 months. Treatment is limited by the blood-brain barrier (BBB) which restricts the passage of most drugs to the brain. We previously reported the design and synthesis of a BBB-penetrant macrocyclic cell-penetrating peptide conjugate (M13) covalently linked at the axial position of a Pt(IV) cisplatin prodrug. Here we show the Pt(IV)-M13 conjugate releases active cisplatin upon intracellular reduction and effects potent in vitro GBM cell killing. Pt(IV)-M13 significantly increased platinum uptake in an in vitro BBB spheroid model and intravenous administration of Pt(IV)-M13 in GBM tumor-bearing mice led to higher platinum levels in brain tissue and intratumorally compared with cisplatin. Pt(IV)-M13 administration was tolerated in naïve nude mice at higher dosage regimes than cisplatin and significantly extended survival above controls in a murine GBM xenograft model (median survival 33 days for Pt(IV)-M13 vs 24 days for Pt(IV) prodrug, 22.5 days for cisplatin and 22 days for control). Increased numbers of γH2AX nuclear foci, biomarkers of DNA damage, were observed in tumors of Pt(IV)-M13-treated mice, consistent with elevated platinum levels. The present work provides the first demonstration that systemic injection of a Pt(IV) complex conjugated to a brain-penetrant macrocyclic peptide can lead to increased platinum levels in the brain and extend survival in mouse GBM models, supporting further development of this approach and the utility of brain-penetrating macrocyclic peptide conjugates for delivering non-BBB penetrant drugs to the central nervous system.
... Pt(IV) complexes show several advantages with respect to Pt(II) counterparts, being more stable and less prone to substitution reactions (Harper et al., 2010). Pt(IV) species are also called pro-drugs because they must be activated by intracellular reduction with the release of the Pt(II) scaffold and the axial ligands (Harper et al., 2010), and dual-action Pt(IV) pro-drugs are obtained when the axial positions are occupied by another relevant biological molecule (another drug, an enzyme inhibitor, a vector, etc) (Neumann et al., 2014;Ma et al., 2015;Wexselblatt et al., 2015;Gibson, 2016;Lee et al., 2018;Lo Re et al., 2018;Montagner et al., 2018;Petruzzella et al., 2018;Savino et al., 2018;Almotairy et al., 2020;Gabano et al., 2021). In this work, we present a facile synthesis of mono glyco-functionalised Pt(IV) complexes based on cisplatin scaffold and their biological applications against osteosarcoma cell lines. ...
The selectivity vs. cancer cells has always been a major challenge for chemotherapeutic agents and in particular for cisplatin, one of the most important anticancer drugs for the treatment of several types of tumors. One strategy to overtake this challenge is to modify the coordination sphere of the metallic center with specific vectors whose receptors are overexpressed in the tumoral cell membrane, such as monosaccharides. In this paper, we report the synthesis of four novel glyco-modified Pt(IV) pro-drugs, based on cisplatin scaffold, and their biological activity against osteosarcoma (OS), a malignant tumor affecting in particular adolescents and young adults. The sugar moiety and the Pt scaffold are linked exploiting the Copper Azide Alkyne Cycloaddition (CUAAC) reaction, which has become the flagship of click chemistry due to its versatility and mild conditions. Cytotoxicity and drug uptake on three different OS cell lines as well as CSCs (Cancer Stem Cell) are described.
... Therefore, platinum complexes that can promote p53 activation are supposed to improve antitumor efficacy of cisplatin. Zhu group designed and synthesized a p53-targeted platinum(IV) complex 57, which is constituted with a cisplatin moiety and a p53 activator chalcone to inhibit the interaction between p53 and human murine double minute 2 (MDM2), serving as the p53 negative regulator (Fig. 15) [163]. Complex 57 showed dramatically increased cytotoxicity on p53 wild-type cancer cells rather than p53 null ones, meanwhile it displayed less toxicity for normal cells. ...
Encouraged by the worldwide success of cisplatin in the field of cancer chemotherapy, intensive works have been conducted to explore more platinum coordination complexes as antitumor drugs over half a century. Although a significant number of promising platinum complexes with multiple structural motifs have been emerging during this period, most of them failed to enter clinical applications. Abandoned reasons for platinum antitumor candidates from experiment to clinic are complicated, and corresponding strategies were proposed during the last decades to deal with those issues. In recent years, with the rapid development of targeted therapy, immunotherapy and so on, anticancer platinum drugs have gained new opportunities and challenges. In this review, we first overviewed the major problems associated with current platinum anticancer drugs including drug resistance, toxicity and side effects to ''know our enemies", and then described recent progresses in rational design of specific-targeted platinum complexes, immune response therapy, tumor microenvironment regulation, light-responsive stimulation, and theranostic therapy as promising strategies to cross these barriers. This review at the interface of chemistry, biology, and medicine points out main problems for current platinum drug development from their action mechanisms , and provides up-to-date potential strategies from drug design perspectives to circumvent those drawbacks, and it is supposed to enlighten researchers with more ideas for future development of highly efficient platinum antitumor complexes.
... In comparison with the control, PPD treatment increases the cell cycle distribution in the G2 phase from 12.89% to 22.60% while cDDP mainly arrest the cell cycle in S phase which is similar to the previous reports. [18][19][20] Since PPD mainly accumulates in the mitochondria, so a further mechanistic investigation is carried out to see its impact on the ultrastructure of TNBC cells using transmission electron microscopy (TEM). As shown in Figure 2A, mitochondria in untreated cells have a complete double-membrane structure, and cristae is perpendicular to the long axis of mitochondrion. ...
... [21] Since PPD preferentially accumulate into mitochondria, so we examined whether PPD treatment can induce mitochondrial lesion in TNBC cells using the real-time polymerase chain reaction (RT-PCR) assay by employing four key regions of mitochondrial genome as reported previously. [18] Two mtDNA fragments of different lengths located in the same genomic region were used as primers. The calculated frequency of the D-loop region which is the major control site of mtDNA is displayed in Figure S12. ...
A mitochondria targeting dual‐action platinumIV prodrug exhibits high anticancer activity in triple negative breast cancer cells. The complex intervenes in several cellular processes including DNA damage, perturbation of mitochondrial bioenergetics and induction of necrosis to kill cancer cells.
... Over the past few decades, researchers have synthesized enormous amount of platinum compounds, and in the meantime more than 30 drugs have already been applied to clinical trials [5]. Although these have showed greater superiority than cisplatin, the inherent drawbacks including poor selectivity and specificity still remain a big challenge [6,7]. It can be seen that simple modification of the molecular structure cannot significantly reduce the drug side effects. ...
The efficiency of producing hydroxyl radicals (·OH) from hydrogen peroxide (H2O2) catalyzed by different iron compounds have been explored extensively. Exclusively, ferrocenecarboxylic acid (FCA) showed the best catalyzed activity for ·OH generation. Then, we designed and prepared near-infrared (NIR) light-responsive and folate-targeted nanoplatform, which co-delivered FCA, cisplatin and indocyanine green (ICG) for improving antitumor therapy through amplified oxidative stress. The noteworthy observation is that under the irradiation of NIR light, the lecithin structure could able to depolymerize through the photothermal conversion mechanism of encapsulated dye ICG, which has achieved an intelligent release of drugs. In addition, the released cisplatin is not only fully effective to damage the DNA of cancer cells but it can able to induce the production of intracellular H2O2, which could further be catalyzed by FCA to generate toxic ·OH for oxidative damage via Fenton and Haber-Weiss reaction. This original strategy may provide an efficient way for improved chemotherapy via amplified oxidative stress.
