The Hippo pathway terminal effector TAZ/WWTR1 mediates oxaliplatin sensitivity in p53 proficient colon cancer cells.

YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the p73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using HCT116 cells, we show here that oxaliplatin treatment led to core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of p73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed antagonistic effects with oxaliplatin in co-treatments. Importantly, using several colorectal cell lines, we show that the sensitizing action of TAZ to oxaliplatin is dependent on the p53 status of the cells. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and p53 activity pushes cells towards apoptosis.

Advancements in steroidal Pt(II) & Pt(IV) derivatives for targeted chemotherapy (2000-2023).

One of the key strategies in chemotherapy involves crosslinking the DNA strands of cancer cells to impede their replication, with platinum (Pt) coordination compounds being a prominent class and cisplatin being its major representative. Steroidal ligands tethered to DNA interactive Pt core act as drug carriers for targeted therapy. While crosslinking of nuclear or mitochondrial DNA strands using coordination complexes has been studied for years, there remains a lack of comprehensive reviews addressing the advancements made in steroidal-Pt derivatives. This review specifically focuses on advancements made in steroid-tethered structural derivatives of Pt(II) or prodrug Pt(IV) for targeted chemotherapy, synthesized between 2000 and 2023. This period was deliberately chosen due to the widespread use of computational techniques for more accurate structure-based drug-design in last two decades. This review discusses the strategy behind tethering steroidal ligands such as testosterone, estrogen, bile acids, and cholesterol to the central DNA interactive Pt core through specific linker groups. The steroidal ligands function as drug delivery vehicles of DNA interactive Pt core and bind with their respective target receptors or proteins that are often overexpressed in cancer cells, thus enabling targeted delivery of Pt moiety to interact with DNA. We discussed structural features such as the location of the linker group on the steroid, the mono, bi, and tridentate configuration of the chelating arm in coordination with Pt, and the rigidity and flexibility of the linker group. The comparative in vitro, in vivo activities, and relative binding affinities of the designed compounds against standard Pt drugs are also discussed. We also provided a critique of observed trends and shortcomings. Our review will provide insights into future molecular designing of targeted DNA crosslinkers and their structural optimization to achieve desired drug properties. From this analysis, we proposed further research directions leading to the future of targeted chemotherapy.

Novel NF-κB Inhibitor-Conjugated Pt(IV) Prodrug to Enable Cancer Therapy through ROS/ER Stress and Mitochondrial Dysfunction and Overcome Multidrug Resistance.

Although cisplatin has been widely used for clinical purposes, its application is limited due to its obvious side effects. To mitigate the defects of cisplatin, here, six "multitarget prodrugs" were synthesized by linking cisplatin and NF-κB inhibitors. Notably, complex 9 demonstrated a 63-fold enhancement in the activity against A549/CDDP cells with lower toxicity toward normal LO2 cells compared to cisplatin. Additionally, complex 9 could effectively cause DNA damage, induce mitochondrial dysfunction, generate reactive oxygen species, and induce cell apoptosis through the mitochondrial pathway and ER stress. Remarkably, complex 9 effectively inhibited the NF-κB/MAPK signaling pathway and disrupted the PI3K/AKT signaling transduction. Importantly, complex 9 showed superior in vivo antitumor efficiency compared to cisplatin or the combination of cisplatin/4, without obvious systemic toxicity in A549 or A549/CDDP xenograft models. Our results demonstrated that the dual-acting mechanism endowed the complexes with high efficiency and low toxicity, which may represent an efficient strategy for cancer therapy.

The Ability of Clinically Relevant Chemotherapeutics to Induce Immunogenic Cell Death in Squamous Cell Carcinoma.

BACKGROUND: Immunogenic cell death (ICD) is a crucial mechanism for triggering the adaptive immune response in cancer patients. Damage-associated molecular patterns (DAMPs) are critical factors in the detection of ICD. Chemotherapeutic drugs can cause ICD and the release of DAMPs. The aim of this study was to assess the potential for paclitaxel and platinum-based chemotherapy regimens to induce ICD in squamous cell carcinoma (SCC) cell lines. In addition, we examined the immunostimulatory effects of clinically relevant chemotherapeutic regimens utilized in the treatment of SCC. METHODS: We screened for differentially expressed ICD markers in the supernatants of three SCC cell lines following treatment with various chemotherapeutic agents. The ICD markers included Adenosine Triphosphate (ATP), Calreticulin (CRT), Annexin A1 (ANXA 1), High Mobility Group Protein B1 (HMGB1), and Heat Shock Protein 70 (HSP70). A vaccination assay was also employed in C57BL/6J mice to validate our in vitro findings. Lastly, the levels of CRT and HMGB1 were evaluated in Serum samples from SCC patients. RESULTS: Addition of the chemotherapy drugs cisplatin (DDP), carboplatin (CBP), nedaplatin (NDP), oxaliplatin (OXA) and docetaxel (DOC) increased the release of ICD markers in two of the SCC cell lines. Furthermore, mice that received vaccinations with cervical cancer cells treated with DDP, CBP, NDP, OXA, or DOC remained tumor-free. Although CBP induced the release of ICD-associated molecules in vitro, it did not prevent tumor growth at the vaccination site in 40% of mice. In addition, both in vitro and in vivo results showed that paclitaxel (TAX) and LBP did not induce ICD in SCC cells. CONCLUSION: The present findings suggest that chemotherapeutic agents can induce an adjuvant effect leading to the extracellular release of DAMPs. Of the agents tested here, DDP, CBP, NDP, OXA and DOC had the ability to act as inducers of ICD.

Comprehensive multi-omics analysis of resectable locally advanced gastric cancer: Assessing response to neoadjuvant camrelizumab and chemotherapy in a single-center, open-label, single-arm phase II trial.

BACKGROUND: The current standard of care for locally advanced gastric cancer (GC) involves neoadjuvant chemotherapy followed by radical surgery. Recently, neoadjuvant treatment for this condition has involved the exploration of immunotherapy plus chemotherapy as a potential approach. However, the efficacy remains uncertain. METHODS: A single-arm, phase 2 study was conducted to evaluate the efficacy and tolerability of neoadjuvant camrelizumab combined with mFOLFOX6 and identify potential biomarkers of response through multi-omics analysis in patients with resectable locally advanced GC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the R0 rate, near pCR rate, progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). Multi-omics analysis was assessed by whole-exome sequencing, transcriptome sequencing, and multiplex immunofluorescence (mIF) using biopsies pre- and post-neoadjuvant therapy. RESULTS: This study involved 60 patients, of which 55 underwent gastrectomy. Among these, five (9.1%) attained a pathological complete response (pCR), and 11 (20.0%) reached near pCR. No unexpected treatment-emergent adverse events or perioperative mortality were observed, and the regimen presented a manageable safety profile. Molecular changes identified through multi-omics analysis correlated with treatment response, highlighting associations between HER2-positive and CTNNB1 mutations with treatment sensitivity and a favourable prognosis. This finding was further supported by immune cell infiltration analysis and mIF. Expression data uncovered a risk model with four genes (RALYL, SCGN, CCKBR, NTS) linked to poor response. Additionally, post-treatment infiltration of CD8+ T lymphocytes positively correlates with pathological response. CONCLUSION: The findings suggest the combination of PD-1-inhibitor and mFOLFOX6 showed efficacy and acceptable toxicity for locally advanced GC. Extended follow-up is required to determine the duration of the response. This study lays essential groundwork for developing precise neoadjuvant regimens.

Joint forces of mass spectrometric techniques (ICP-MS and MALDI-TOF-MS) and fluorescence spectrometry in the study of platinum-based cytostatic drugs interactions with metallothionein MT2 and MT3.

Herby, the interaction of metallothioneins with commonly used Pt-based anticancer drugs - cisplatin, carboplatin, and oxaliplatin - was investigated using the combined power of elemental (i.e. LA-ICP-MS, CE-ICP-MS) and molecular (i.e. MALDI-TOF-MS) analytical techniques providing not only required information about the interaction, but also the benefit of low sample consumption. The amount of Cd and Pt incorporated within the protein was determined for protein monomers and dimer/oligomers formed by non-oxidative dimerization. Moreover, fluorescence spectrometry using Zn2+-selective fluorescent indicator - FluoZin3 - was employed to monitor the ability of Pt drugs to release natively occurring Zn from the protein molecule. The investigation was carried out using two protein isoforms (i.e. MT2, MT3), and significant differences in behaviour of these two isoforms were observed. The main attention was paid to elucidating whether the protein dimerization/oligomerization may be the reason for the potential failure of the anticancer therapy based on these drugs. Based on the results, it was demonstrated that the interaction of MT2 (both monomers and dimers) interacted with Pt drugs significantly less compared to MT3 (both monomers and dimers). Also, a significant difference between monomeric and dimeric forms (both MT2 and MT3) was not observed. This may suggest that dimer formation is not the key factor leading to the inactivation of Pt drugs.

Promising Anticancer Prodrugs Based on Pt(IV) Complexes with Bis-organosilane Ligands in Axial Positions.

We report two novel prodrug Pt(IV) complexes with bis-organosilane ligands in axial positions: cis-dichloro(diamine)-trans-[3-(triethoxysilyl)propylcarbamate]platinum(IV) (Pt(IV)-biSi-1) and cis-dichloro(diisopropylamine)-trans-[3-(triethoxysilyl) propyl carbamate]platinum(IV) (Pt(IV)-biSi-2). Pt(IV)-biSi-2 demonstrated enhanced in vitro cytotoxicity against colon cancer cells (HCT 116 and HT-29) compared with cisplatin and Pt(IV)-biSi-1. Notably, Pt(IV)-biSi-2 exhibited higher cytotoxicity toward cancer cells and lower toxicity on nontumorigenic intestinal cells (HIEC6). In preclinical mouse models of colorectal cancer, Pt(IV)-biSi-2 outperformed cisplatin in reducing tumor growth at lower concentrations, with reduced side effects. Mechanistically, Pt(IV)-biSi-2 induced permanent DNA damage independent of p53 levels. DNA damage such as double-strand breaks marked by histone gH2Ax was permanent after treatment with Pt(IV)-biSi-2, in contrast to cisplatin's transient effects. Pt(IV)-biSi-2's faster reduction to Pt(II) species upon exposure to biological reductants supports its superior biological response. These findings unveil a novel strategy for designing Pt(IV) anticancer prodrugs with enhanced activity and specificity, offering therapeutic opportunities beyond conventional Pt drugs.

Gemfibrozil-Platinum(IV) Precursors for New Enhanced-Starvation and Chemotherapy In Vitro and In Vivo.

A brand-new enhanced starvation is put forward to trigger sensitized chemotherapy: blocking tumor-relation blood vessel formation and accelerating nutrient degradation and efflux. Following this concept, two cisplatin-like gemfibrozil-derived Pt(IV) prodrugs, GP and GPG, are synthesized. GP and GPG had nanomolar IC50 against A2780 cells and higher selectivity against normal cells than cisplatin. Bioactivity results confirmed that GP and GPG highly accumulated in cells and induced DNA damage, G2-phase arrest, and p53 expression. Besides, they could increase ROS and MDA levels and reduce mitochondrial membrane potential and Bcl-2 expression to promote cell apoptosis. In vivo, GP showed superior antitumor activity in A2780 tumor-bearing mice with no observable tissue damage. Mechanistic studies suggested that highly selective chemotherapy could be due to the new enhanced starvation effect: blocking vasculature formation via inhibiting the CYP2C8/EETs pathway and VEGFR2, NF-κB, and COX-2 expression and cholesterol efflux and degradation acceleration via increasing ABCA1 and PPARα.

Click-Capable Phenanthriplatin Derivatives as Tools to Study Pt(II)-Induced Nucleolar Stress.

It is well established that oxaliplatin, one of the three Pt(II) anticancer drugs approved worldwide, and phenanthriplatin, an important preclinical monofunctional Pt(II) anticancer drug, possess a different mode of action from that of cisplatin and carboplatin, namely, the induction of nucleolar stress. The exact mechanisms that lead to Pt-induced nucleolar stress are, however, still poorly understood. As such, studies aimed at better understanding the biological targets of both oxaliplatin and phenanthriplatin are urgently needed to expand our understanding of Pt-induced nucleolar stress and guide the future design of Pt chemotherapeutics. One approach that has seen great success in the past is the use of Pt-click complexes to study the biological targets of Pt drugs. Herein, we report the synthesis and characterization of the first examples of click-capable phenanthriplatin complexes. Furthermore, through monitoring the relocalization of nucleolar proteins, RNA transcription levels, and DNA damage repair biomarker γH2AX, and by investigating their in vitro cytotoxicity, we show that these complexes successfully mimic the cellular responses observed for phenanthriplatin treatment in the same experiments. The click-capable phenanthriplatin derivatives described here expand the existing library of Pt-click complexes. Significantly they are suitable for studying nucleolar stress mechanisms and further elucidating the biological targets of Pt complexes.

Two Hematological Markers Predicting the Efficacy and Prognosis of Neoadjuvant Chemotherapy Using Lobaplatin Against Triple-Negative Breast Cancer.

BACKGROUND: Our previous work indicated that the addition of lobaplatin to combined therapy with taxane and anthracycline can improve the pathological complete response rate of neoadjuvant therapy for triple-negative breast cancer (TNBC) and lengthen long-term survival significantly, but the therapeutic markers of this regimen are unclear. METHODS: Eighty-three patients who met the inclusion criteria were included in this post hoc analysis. We analyzed the association between platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) before neoadjuvant chemotherapy with the efficacy and prognosis after treatment with docetaxel, epirubicin, and lobaplatin neoadjuvant chemotherapy regimen. χ2 test and Cox regression were used to analyze the association between PLR and NLR with total pathologic complete response (tpCR), as well as the association between PLR and NLR with event-free survival (EFS) and overall survival (OS), respectively. RESULTS: The tpCR rate in the PLR- group was 49.0% (25/51), which was significantly higher than that in the PLR+ group (25.0% [8/32], P = .032). The tpCR rate in the NLR- group was 49.1% (26/53), which was significantly higher than that in the NLR+ group (23.3% [7/30], P = .024). The tpCR rate of the PLR-NLR- (PLR- and NLR-) group was 53.7% (22/41), which was significantly higher than that of the PLR+/NLR+ (PLR+ or/and NLR+) group (26.1% [11/42]; P = .012). EFS and OS in the NLR+ group were significantly shorter than those in the NLR- group (P = .028 for EFS; P = .047 for OS). Patients in the PLR-NLR- group had a longer EFS than those in the PLR+/NLR+ group (P = .002). CONCLUSION: PLR and NLR could be used to predict the efficacy of neoadjuvant therapy with the taxane, anthracycline, and lobaplatin regimen for patients with TNBC, as patients who had lower PLR and NLR values had a higher tpCR rate and a better long-term prognosis.

A monofunctional Pt(II) complex combats triple negative breast cancer by triggering lysosome-dependent cell death.

Monofunctional Pt(II) complexes with potent efficacy to overcome the drawbacks of current platinum drugs represent a promising therapeutic approach for triple negative breast cancer (TNBC). A heterocyclic-ligated monofunctional Pt(II) complex PtL with a unique action of mode was designed and investigated. PtL induced DNA single-strand breaks and caused genomic instability in TNBC cells. Mechanism studies demonstrated that PtL disrupted lysosomal acidity and function, which in turn triggered lysosome-dependent cell death. Furthermore, PtL showed convincing suppression in the tube forming and cell migratory abilities against the metastatic potential of TNBC cells. The synthesis and investigation of PtL revealed its potential value as an anti-TNBC drug and extended the family of monofunctional Pt(II) complexes.

A Nanoscale Trans-Platinum(II)-Based Supramolecular Coordination Self-Assembly with a Distinct Anticancer Mechanism.

Drug resistance significantly hampers the clinical application of existing platinum-based anticancer drugs. New platinum medications that possess distinct mechanisms of action are highly desired for the treatment of Pt-resistant cancers. Herein, a nanoscale trans-platinum(II)-based supramolecular coordination self-assembly (Pt-TCPP-BA) is prepared via using trans-[PtCl2(pyridine)(NH3)] (transpyroplatin), tetracarboxylporphyrin (TCPP), and benzoic acid (BA) as building blocks to combat drug resistance in platinum-based chemotherapy. Mechanistic studies indicate that Pt-TCPP-BA shows a hydrogen-peroxide-responsive dissociation behavior along with the generation of bioactive trans-Pt(II) and TCPP-Pt species. Different from cisplatin, these degradation products interact with DNA via interstrand cross-links and small groove binding, and induce significant upregulation of cell-death-related proteins such as p53, cleaved caspase 3, p21, and phosphorylated H2A histone family member X in cisplatin-resistant cancer cells. As a result, Pt-TCPP-BA exhibits potent killing effects against Pt-resistant tumors both in vitro and in vivo. Overall, this work not only provides a new platinum drug for combating drug-resistant cancer but also offers a new paradigm for the development of platinum-based supramolecular anticancer drugs.

Effect of substituents on the 1O2 production and biological activity of (N

Twelve (N^N^N)platinum pyridyl complexes, (N^N^N)Pt(pyF), were synthesised and investigated for their singlet oxygen generation and potential biological activities. They exhibited 1IL and 1MLCT absorption transitions at approximately 325 and 360 nm, identified through TD-DFT calculations. Luminescence was observed only in the L1-derived compounds in solution, with a dual emission with the main contribution of phosphorescence under deaerated conditions. Room temperature phosphorescence was detected in all solid-state cases. Electron-withdrawing substituents at specific positions (R1 and X) and the number of fluorine atoms in R2 were found to enhance the photosensitizing capabilities of these compounds. Biological assessments, including cytotoxicity and photocytotoxicity, were conducted to evaluate their potential as chemotherapeutic agents and photosensitizers. Complexes with chloro substitution in the N^N^N tridentate ligand of the central pyridine ring exhibited promising chemotherapeutic properties. Ancillary pyridine ring substitution became significant under irradiation conditions, with fluoromethylated substituents enhancing cytotoxicity. Complex 2-CF3 was the most efficient singlet oxygen producer and a highly effective photosensitizer. CHF2-substituted complexes also showed improved photosensitizing activity. DNA binding studies indicated moderate interactions with DNA, offering insights into potential biological applications.

Synthesis and anticancer mechanisms of four novel platinum(II) 4'-substituted-2,2':6',2''-terpyridine complexes.

Mitophagy, a selective autophagic process, has emerged as a pathway involved in degrading dysfunctional mitochondria. Herein, new platinum(II)-based chemotherapeutics with mitophagy-targeting properties are proposed. Four novel binuclear anticancer Pt(II) complexes with 4'-substituted-2,2':6',2''-terpyridine derivatives (tpy1-tpy4), i.e., [Pt2(tpy1)(DMSO)2Cl4]·CH3OH (tpy1Pt), [Pt(tpy2)Cl][Pt(DMSO)Cl3]·CH3COCH3 (tpy2Pt), [Pt(tpy3)Cl][Pt(DMSO)Cl3] (tpy3Pt), and [Pt(tpy4)Cl]Cl·CH3OH (tpy4Pt), were designed and prepared. Moreover, their potential antitumor mechanism was studied. Tpy1Pt-tpy4Pt exhibited more selective cytotoxicity against cisplatin-resistant SK-OV-3/DDP (SKO3cisR) cancer cells compared with those against ovarian SK-OV-3 (SKO3) cancer cells and normal HL-7702 liver (H702) cells. This selective cytotoxicity of Tpy1Pt-tpy4Pt was better than that of its ligands (i.e., tpy1-tpy4), the clinical drug cisplatin, and cis-Pt(DMSO)2Cl2. The results of various experiments indicated that tpy1Pt and tpy2Pt kill SKO3cisR cancer cells via a mitophagy pathway, which involves the disruption of the mitophagy-related protein expression, dissipation of the mitochondrial membrane potential, elevation of the [Ca2+] and reactive oxygen species levels, promotion of mitochondrial DNA damage, and reduction in the adenosine triphosphate and mitochondrial respiratory chain levels. Furthermore, in vivo experiments indicated that the dinuclear anticancer Pt(II) coordination compound (tpy1Pt) has remarkable therapeutic efficiency (ca. 52.4%) and almost no toxicity. Therefore, the new 4'-substituted-2,2':6',2''-terpyridine Pt(II) coordination compound (tpy1Pt) is a potential candidate for next-generation mitophagy-targeting dinuclear Pt(II)-based anticancer drugs.

Improving In Vivo Tumor Accumulation and Efficacy of Platinum Antitumor Agents by Electronic Tuning of the Kinetic Lability.

The impact of kinetic lability or reactivity on in vitro cytotoxicity, stability in plasma, in vivo tumor and tissue accumulation, and antitumor efficacy of functional platinum(II) (Pt) anticancer agents containing a O˄O ß-diketonate leaving ligand remain largely unexplored. To investigate this, we synthesized Pt complexes [(NH3 )2 Pt(L1-H)]NO3 and [(DACH)Pt(L1-H)]NO3 (L1=4,4,4-trifluoro-1-ferrocenylbutane-1,3-dione, DACH=1R,2R-cyclohexane-1,2-diamine) containing an electron deficient [L1-H]- O˄O leaving ligand and [(NH3 )2 Pt(L2-H)]NO3 and [(DACH)Pt(L2-H)]NO3 (L2=1-ferrocenylbutane-1,3-dione) containing an electron-rich [L2-H]- O˄O leaving ligand. While all four complexes have comparable lipophilicity, the presence of the electron-withdrawing CF3 group was found to dramatically enhance the reactivity of these complexes toward nucleophilic biomolecules. In vitro cellular assays revealed that the more reactive complexes have higher cellular uptake and higher anticancer potency as compared to their less reactive analogs. But the scenario is opposite in vivo, where the less reactive complex showed improved tissue and tumor accumulation and better anticancer efficacy in mice bearing ovarian xenograft when compared to its more reactive analog. Finally, in addition to demonstrating the profound but contrasting impact of kinetic lability on in vitro and in vivo antitumor potencies, we also described the impact of kinetic lability on the mechanism of action of this class of promising antitumor agents.

Highly photoactive Ir(III)-Pt(IV) heterometallic conjugates for anticancer therapy.

For the first time, this study reported the photoactivatable activity of Ir(III)-Pt(IV) heterometallic conjugates, which were stable in the dark and activated to release oxaliplatin and Ir within 3 min of irradiation. The conjugates induced apoptosis and immunologic cell death through Pt-DNA binding and reactive oxygen species generation upon irradiation. This work developed photoactivatable heterometallic agents for anticancer therapy.

Adenine-adenine, adenine-cytosine and cytosine-cytosine intrastrand crosslinks induced by a photoactivatable Pt(IV) anticancer prodrug.

Four trinucleotides 5'-ATA-3' (I), 5'-ATC-3' (II), 5'-CTA-3' (III) and 5'-CTC-3' (IV) were introduced to interact with a diazido-based photoactivatable anticancer prodrug trans,trans,trans-[PtIV(N3)2(OH)2(py)2] (py = pyridine; 1) upon light irradiation. Using electrospray ionization mass spectrometry (ESI-MS), we aimed to investigate the possibility of 1,3-intrastrand crosslinks at adenine and/or cytosine in the trinucleotides via the bi-functional trans-[PtII(py)2]2+ species generated by photodecomposition of complex 1. The primary mass spectrometry results showed that although mono- and di-platinated trinucleotides bound by mono-functional trans-[PtII(N3)(py)2]+ species were the major platinated adducts, comparable amounts of bifunctional trans-[PtII(py)2]2+-bound trinucleotides were also observed. Further tandem mass spectrometry of the trans-[PtII(py)2]2+-bound trinucleotides showed the formation of 1,3-crosslinks between adenine-adenine, adenine-cytosine and cytosine-cytosine bases in the trinucleotides. The formation of such unique structures is not only distinct from the action modes of cisplatin with DNA but also an important complement to the acknowledged 1,3-GNG intrastrand crosslink by trans-Pt species, which may support the promising and distinct anticancer activities of such photoactivatable diazido Pt(IV) anticancer prodrugs and deserve further studies.

Compatibility of Nucleobases Containing Pt(II) Complexes with Red Blood Cells for Possible Drug Delivery Applications.

The therapeutic advantages of some platinum complexes as major anticancer chemotherapeutic agents and of nucleoside analogue-based compounds as essential antiviral/antitumor drugs are widely recognized. Red blood cells (RBCs) offer a potential new strategy for the targeted release of therapeutic agents due to their biocompatibility, which can protect loaded drugs from inactivation in the blood, thus improving biodistribution. In this study, we evaluated the feasibility of loading model nucleobase-containing Pt(II) complexes into human RBCs that were highly stabilized by four N-donors and susceptible to further modification for possible antitumor/antiviral applications. Specifically, platinum-based nucleoside derivatives [PtII(dien)(N7-Guo)]2+, [PtII(dien)(N7-dGuo)]2+, and [PtII(dien)(N7-dGTP)] (dien = diethylenetriamine; Guo = guanosine; dGuo = 2'-deoxy-guanosine; dGTP = 5'-(2'-deoxy)-guanosine-triphosphate) were investigated. These Pt(II) complexes were demonstrated to be stable species suitable for incorporation into RBCs. This result opens avenues for the possible incorporation of other metalated nucleobases analogues, with potential antitumor and/or antiviral activity, into RBCs.

The inhibitory effects of platinum(II) complexes on amyloid aggregation: a theoretical and experimental approach.

Platinum (Pt)(II) square planar complexes are well-known anticancer drugs whose Mechanism of Action (MOA) are finely tuned by the polar, hydrophobic and aromatic features of the ligands. In the attempt to translate this tunability to the identification of potential neurodrugs, herein, four Pt(II) complexes were investigated in their ability to modulate the self-aggregation processes of two amyloidogenic models: Sup35p7-13 and NPM1264-277 peptides. In particular, phenanthriplatin revealed the most efficient agent in the modulation of amyloid aggregation: through several biophysical assays, as Thioflavin T (ThT), electrospray ionization mass spectrometry (ESI-MS) and ultraviolet-visible (UV-vis) absorption spectroscopy, this complex revealed able to markedly suppress aggregation and to disassemble small soluble aggregates. This effect was due to a direct coordination of phenanthriplatin to the amyloid, with the loss of several ligands and different stoichiometries, by the formation of π-π and π-cation interactions as indicated from molecular dynamic simulations. Presented data support a growing and recent approach concerning the repurposing of metallodrugs as potential novel neurotherapeutics.

The mechanism of antiproliferative activity of the oxaliplatin pyrophosphate derivative involves its binding to nuclear DNA in cancer cells.

(1R,2R-diaminocyclohexane)(dihydropyrophosphato) platinum(II), also abbreviated as RRD2, belongs to a class of potent antitumor platinum cytostatics called phosphaplatins. Curiously, several published studies have suggested significant mechanistic differences between phosphaplatins and conventional platinum antitumor drugs. Controversial findings have been published regarding the role of RRD2 binding to DNA in the mechanism of its antiproliferative activity in cancer cells. This prompted us to perform detailed studies to confirm or rule out the role of RRD2 binding to DNA in its antiproliferative effect in cancer cells. Here, we show that RRD2 exhibits excellent antiproliferative activity in various cancer cell lines, with IC50 values in the low micromolar or submicromolar range. Moreover, the results of this study demonstrate that DNA lesions caused by RRD2 contribute to killing cancer cells treated with this phosphaplatin derivative. Additionally, our data indicate that RRD2 accumulates in cancer cells but to a lesser extent than cisplatin. On the other hand, the efficiency of cisplatin and RRD2, after they accumulate in cancer cells, in binding to nuclear DNA is similar. Our results also show that RRD2 in the medium, in which the cells were cultured before RRD2 accumulated inside the cells, remained intact. This result is consistent with the view that RRD2 is activated by releasing free pyrophosphate only in the environment of cancer cells, thereby allowing RRD2 to bind to nuclear DNA.