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 Platinum-Aluminum Bimetallic Salen Complex for Pro-senescence Cancer Therapy.

Cell senescence is defined as irreversible cell cycle arrest, which can be triggered by telomere shortening or by various types of genotoxic stress. Induction of senescence is emerging as a new strategy for the treatment of cancer, especially when sequentially combined with a second senolytic drug capable of killing the resulting senescent cells, however severely suffering from the undesired off-target side effects from the senolytic drugs. Here, we prepare a bimetalic platinum-aluminum salen complex (Alumiplatin) for cancer therapy-a combination of pro-senesence chemotherapy with in situ senotherapy to avoid the side effects. The aluminum salen moiety, as a G-quadruplex stabilizer, enhances the salen's ability to induce cancer cell senescence and this phenotype is in turn sensitive to the cytotoxic activity of the monofunctional platinum moiety. It exhibits an excellent capability for inducing senescence, a potent cytotoxic activity against cancer cells both in vitro and in vivo, and an improved safety profile compared to cisplatin. Therefore, Alumiplatin may be a good candidate to be further developed into safe and effective anticancer agents. This novel combination of cell senescence inducers with genotoxic drugs revolutionizes the therapy options of designing multi-targeting anticancer agents to improve the efficacy of anticancer therapies.

Inhibition of Chk1 stimulates cytotoxic action of platinum-based drugs and TRAIL combination in human prostate cancer cells.

Checkpoint kinase 1 (Chk1) plays an important role in regulation of the cell cycle, DNA damage response and cell death, and represents an attractive target in anticancer therapy. Small-molecule inhibitors of Chk1 have been intensively investigated either as single agents or in combination with various chemotherapeutic drugs and they can enhance the chemosensitivity of numerous tumor types. Here we newly demonstrate that pharmacological inhibition of Chk1 using potent and selective inhibitor SCH900776, currently profiled in phase II clinical trials, significantly enhances cytotoxic effects of the combination of platinum-based drugs (cisplatin or LA-12) and TRAIL (tumor necrosis factor-related apoptosis inducing ligand) in human prostate cancer cells. The specific role of Chk1 in the drug combination-induced cytotoxicity was confirmed by siRNA-mediated silencing of this kinase. Using RNAi-based methods we also showed the importance of Bak-dependent mitochondrial apoptotic pathway in the combined anticancer action of SCH900776, cisplatin and TRAIL. The triple drug combination-induced cytotoxicity was partially enhanced by siRNA-mediated Mcl-1 silencing. Our findings suggest that targeting Chk1 may be used as an efficient strategy for sensitization of prostate cancer cells to killing action of platinum-based chemotherapeutic drugs and TRAIL.

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.

Synthesis, Characterization, and Cytotoxicity Evaluation of Novel Water-Soluble Cationic Platinum(II) Organometallic Complexes with Phenanthroline and Imidazolic Ligands.

Platinum-based chemotherapeutic agents are widely used in the treatment of cancer. However, their effectiveness is limited by severe adverse reactions, drug resistance, and poor water solubility. This study focuses on the synthesis and characterization of new water-soluble cationic monofunctional platinum(II) complexes starting from the [PtCl(η1-C2H4OEt)(phen)] (1, phen=1,10-phenanthroline) precursor, specifically [Pt(NH3)(η1-C2H4OEt)(phen)]Cl (2), [Pt(1-hexyl-1H-imidazole)(η1-C2H4OEt)(phen)]Cl (3), and [Pt(1-hexyl-1H-benzo[d]imidazole)(η1-C2H4OEt)(phen)]Cl (4), which deviate from traditional requirements for antitumor activity. These complexes were evaluated for their cytotoxic effects in comparison to cisplatin, using immortalized cervical adenocarcinoma cells (HeLa), human renal carcinoma cells (Caki-1), and normal human renal cells (HK-2). While complex 2 showed minimal effects on the cell lines, complexes 3 and 4 demonstrated higher cytotoxicity than cisplatin. Notably, complex 4 displayed the highest cytotoxicity in both cancer and normal cell lines. However, complex 3 exhibited the highest selectivity for renal tumor cells (Caki-1) among the tested complexes, compared to healthy cells (HK-2). This resulted in a significantly higher selectivity than that of cisplatin and complex 4. Therefore, complex 3 shows potential as a leading candidate for the development of a new generation of platinum-based anticancer drugs, utilizing biocompatible imidazole ligands while demonstrating promising anticancer properties.

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.

Nanocomposite Hydrogel Bioinks for 3D Bioprinting of Tumor Models.

In vitro tumor models were successfully constructed by 3D bioprinting; however, bioinks with proper viscosity, good biocompatibility, and tunable biophysical and biochemical properties are highly desirable for tumor models that closely recapitulated the main features of native tumors. Here, we developed a nanocomposite hydrogel bioink that was used to construct ovarian and colon cancer models by 3D bioprinting. The nanocomposite bioink was composed of aldehyde-modified cellulose nanocrystals (aCNCs), aldehyde-modified hyaluronic acid (aHA), and gelatin. The hydrogels possessed tunable gelation time, mechanical properties, and printability by controlling the ratio between aCNCs and gelatin. In addition, ovarian and colorectal cancer cells embedded in hydrogels showed high survival rates and rapid growth. By the combination of 3D bioprinting, ovarian and colorectal tumor models were constructed in vitro and used for drug screening. The results showed that gemcitabine had therapeutic effects on ovarian tumor cells. However, the ovarian tumor model showed drug resistance for oxaliplatin treatment.

Photodynamic Effect of Amphiphilic N∧C∧N-Coordinated Platinum(II) Complexes in Human Umbilical Vein Endothelial Cells.

Here, we report a photodynamic therapy (PDT) photosensitizer of N∧C∧N-coordinated Pt(II) complexes: [Pt(L)(solv)]+ (HL = 1,3-(2-dipyridyl)benzene) and [Pt(L)]+@HSA, which is the Pt(II) complex encapsulated in human serum albumin (HSA). The quantum yield of singlet oxygen production for [Pt(L)(solv)]+ is more than 50%, while that for [Pt(L)]+@HSA is much lower. Photoimages of human umbilical vein endothelial cells (HUVECs) treated with the Pt(II) complexes suggest that [Pt(L)(solv)]+ is delocalized in the entire cell after the fast uptake by diffusion and [Pt(L)]+@HSA is taken up by endocytosis and localized on organelles and the cell membrane. [Pt(L)(solv)]+ shows high photocytotoxicity for HUVECs, while [Pt(L)]+@HSA does not show photocytotoxicity.

Multiaction Pt(IV) Complexes: Cytotoxicity in Ovarian Cancer Cell Lines and Mechanistic Studies.

Ovarian cancer has the worst case-to-fatality ratio of all gynecologic malignancies. The main reasons for the high mortality rate are relapse and the development of chemoresistance. In this paper, the cytotoxic activity of two new multiaction platinum(IV) derivatives of cisplatin and oxaliplatin in a panel of ovarian cancer cells is reported. Cis,cis,trans-[Pt(NH3)2Cl2(IPA)(DCA)] (1) and trans-[Pt(DACH)(OX)(IPA)(DCA)] (2) (IPA = indole-3-propionic acid, DCA = dichloroacetate, DACH = 1R,2R-1,2-diaminocyclohexane, OX = oxalate) were synthesized and characterized by elemental analysis, ESI-MS, FT-IR, and 1H, 13C, and195Pt NMR spectroscopy. The biological activity was evaluated in A2780, PEA1, PEA2, SKOV3, SW626, and OVCAR3 cells. Both complexes are potent cytotoxins. Remarkably, complex 2 is 14 times more active in OVCAR3 cells than cisplatin and is able to overcome cisplatin resistance in PEA2 and A2780cis cells, which are models of post-treatment patient-developed and laboratory-induced resistance. This complex also shows activity in 3D cancer models of the A2780 cells. Mechanistic studies revealed that the complexes induce apoptosis via DNA damage and ROS generation.

Advancements in platinum-based anticancer drug development: A comprehensive review of strategies, discoveries, and future perspectives.

Platinum-based anticancer drugs have been at the forefront of cancer chemotherapy, with cisplatin emerging as a pioneer in the treatment of various malignancies. This review article provides a comprehensive overview of the evolution of platinum-based anticancer therapeutics, focusing on the development of cisplatin, platinum(IV) prodrugs, and the integration of photodynamic therapy (PDT) for enhanced cancer treatment results. The first section of the review delves into the historical context and molecular mechanisms underlying the success of cisplatin, highlighting its DNA binding properties and subsequent interference with cellular processes. Despite its clinical efficacy, the inherent limitations, including dose-dependent toxicities and acquired resistance, accelerated the exploration of novel platinum derivatives. This led to the emergence of platinum(IV) prodrugs, designed to overcome resistance mechanisms and enhance selectivity through targeted drug delivery. The subsequent section provides an in-depth analysis of the principles of design and structural modifications employed in the development of platinum(IV) prodrugs. The transitions to the incorporation of photodynamic therapy (PDT) stands out as a synergistic approach to platinum-based anticancer treatment. The photophysical properties of platinum complexes are discussed in the context of their potential application in PDT, emphasizing on combined cytotoxic effects of platinum-based drugs and light-induced reactive oxygen species generation. This dual-action approach holds great promise for overcoming the limitations of traditional chemotherapy as well as producing superior therapeutic outcomes. Overall, the present report explores the latest developments in the development and use of platinum complexes, highlighting novel strategies such combination treatments, targeted delivery methods, and the generation of multifunctional complexes. It also provides a comprehensive overview of the current landscape while proposing future directions for the development of next-generation platinum-based anticancer therapeutics.

Palladium and platinum complexes based on pyridine bases induced anticancer effectiveness via apoptosis protein signaling in cancer cells.

Palladium and platinum complexes, especially those that include cisplatin, can be useful chemotherapeutic drugs. Alternatives that have less adverse effects and require lower dosages of treatment could be provided by complexes containing pyridine bases. The complexes [Pd(SCN)2(4-Acpy)2] (1), [Pd(N3)2(4-Acpy)2] (2) [Pd(paOH)2].2Cl (3) and [Pt(SCN)2(paO)2] (4) were prepared by self-assembly method at ambient temperature; (4-Acpy = 4-acetylpyridine and paOH = pyridine-2-carbaldehyde-oxime). The structure of complexes 1-4 was confirmed using spectroscopic and X-ray crystallography methods. Complexes 1-4 have similar features in isomerism that include the trans coordination geometry of pyridine ligands with Pd or Pt ion. The 3D network structure of complexes 1-4 was constructed by an infinite number of discrete mononuclear molecules extending via H-bonds. The Pd and Pt complexes 1-4 with pyridine ligands were assessed on MCF-7, T47D breast cancer cells and HCT116 colon cancer cells. The study evaluated cell death through apoptosis and cell cycle phases in MCF-7 cells treated with palladium or platinum conjugated with pyridine base. Upon treatment of MCF-7 with these complexes, the expression of apoptotic signals (Bcl2, p53, Bax and c-Myc) and cell cycle signals (p16, CDK1A, CDK1B) were evaluated. Compared to other complexes and cisplatin, IC50 of complex 1 was lowest in MCF-7 cells and complex 2 in T47D cells. Complex 4 has the highest effectiveness on HCT116. The selective index (SI) of complexes 1-4 has a value of more than two for all cancer cell lines, indicating that the complexes were less toxic to normal cells when given the same dose. MCF-7 cells treated with complex 2 and platinum complex 4 exhibited the highest level of early apoptosis. p16 may be signal arrest cells in Sub G, which was observed in cells treated with palladium complexes that suppress excessive cell proliferation. High c-Myc expression of treated cells with four complexes 1-4 and cisplatin could induce p53. All complexes 1-4 elevated the expression of Bax and triggered by the tumor suppressor gene p53. p53 was downregulating the expression of Bcl2.

Novel Pt(IV) complexes containing salvigenin ligand reverse cisplatin-induced resistance by inhibiting Rap1b-mediated cancer cell stemness in esophageal squamous cell carcinoma treatments.

Esophageal squamous cell carcinoma (ESCC) is a malignant tumor that is highly susceptible to metastasis, recurrence and resistance, and few therapeutic targets have been identified and proven effective. Herein, we demonstrated for the first time that Rap1b can positively regulate ESCC cell stemness, as well as designed and synthesized a novel class of Pt(IV) complexes that can effectively inhibit Raplb. In vitro biological studies showed that complex-1 exhibited stronger cytotoxicity than cisplatin and oxaliplatin against a variety of ESCC cells, and effectively reversed cisplatin-induced resistance of TE6 cells by increasing cellular accumulation of platinum and inhibiting cancer cell stemness. Significantly, complex-1 also exhibited strong ability to reversal cisplatin-induced cancer cell resistance and inhibit tumor growth in TE6/cDDP xenograft mice models, with a tumor growth inhibition rate of 73.3 % at 13 mg/kg and did not show significant systemic toxicity. Overall, Rap1b is a promising target to be developed as an effective treatment for ESCC. Complex-1, as the first Pt(IV) complex that can strongly inhibit Rap1b, is also worthy of further in-depth study.

Evaluation of anticancer activity of novel platinum(II) bis(thiosemicarbazone) complex against breast cancer.

The study aims to synthesize a novel bis(thiosemicarbazone) derivative based on platinum (thioPt) and evaluate its anticancer properties against MFC-7 and MDA-MB-231 breast cancer cells. A new platinum complex was synthesised by reacting K2PtCl4 with 2,2'-(1,2-diphenylethane-1,2-diylidene)bis(hydrazine-1-carbothioamide) in ethanol in the presence of K2CO3. In the obtained complex, the platinum atom is coordinated by a conjugated system = N-NC-S-The structures of the new compound were characterised using NMR spectroscopy, HR MS, IR, and X-ray structural analysis. The obtained results of the cytotoxicity assay indicate that compound thioPt had potent anticancer activity (MCF-7: 61.03 ± 3.57 µM, MDA-MB-231: 60.05 ± 5.40 µM) with less toxicity against normal MCF-10A breast epithelial cells, even compared to the reference compound (cisplatin). In addition, subsequent experiments found that thioPt induces apoptosis through both an extrinsic (↑caspase 8 activity) and intrinsic (↓ΔΨm) pathway, which ultimately leads to an increase in active caspase 3/7 levels. The induction of autophagy and levels of proteins involved in this process (LC3A/B and Beclin-1) were examined in MCF-7 and MDA-MB-231 breast cancer cells exposed to tested compounds (thio, thioPt, cisPt) at a concentration of 50 µM for 24 h. Based on these results, it can be concluded that thio and thioPt do not significantly affect the autophagy process. This demonstrates their superiority over cisplatin, which can stimulate cancer cell survival through its effect on stimulation of autophagy.

Platinum(II) N-heterocyclic carbene complexes arrest metastatic tumor growth.

Vimentin is a cytoskeletal intermediate filament protein that plays pivotal roles in tumor initiation, progression, and metastasis, and its overexpression in aggressive cancers predicted poor prognosis. Herein described is a highly effective antitumor and antimetastatic metal complex [PtII(C^N^N)(NHC2Bu)]PF6 (Pt1a; HC^N^N = 6-phenyl-2,2'-bipyridine; NHC= N-heterocyclic carbene) that engages vimentin via noncovalent binding interactions with a distinct orthogonal structural scaffold. Pt1a displays vimentin-binding affinity with a dissociation constant of 1.06 µM from surface plasmon resonance measurements and fits into a pocket between the coiled coils of the rod domain of vimentin with multiple hydrophobic interactions. It engages vimentin in cellulo, disrupts vimentin cytoskeleton, reduces vimentin expression in tumors, suppresses xenograft growth and metastasis in different mouse models, and is well tolerated, attributable to biotransformation to less toxic and renal-clearable platinum(II) species. Our studies uncovered the practical therapeutic potential of platinum(II)‒NHC complexes as effective targeted chemotherapy for combating metastatic and cisplatin-resistant cancers.

Interactions with DNA Models of the Oxaliplatin Analog (cis-1,3-DACH)PtCl2.

It is generally accepted that adjacent guanine residues in DNA are the primary target for platinum antitumor drugs and that differences in the conformations of the Pt-DNA adducts can play a role in their antitumor activity. In this study, we investigated the effect of the carrier ligand cis-1,3-diaminocyclohexane (cis-1,3-DACH) upon formation, stability, and stereochemistry of the (cis-1,3-DACH)PtG2 and (cis-1,3-DACH)Pt(d(GpG)) adducts (G = 9-EthlyGuanine, guanosine, 5'- and 3'-guanosine monophosphate; d(GpG) = deoxyguanosil(3'-5')deoxyguanosine). A peculiar feature of the cis-1,3-DACH carrier ligand is the steric bulk of the diamine, which is asymmetric with respect to the Pt-coordination plane. The (cis-1,3-DACH)Pt(5'GMP)2 and (cis-1,3-DACH)Pt(3'GMP)2 adducts show preference for the ΛHT and ∆HT conformations, respectively (HT stands for Head-to-Tail). Moreover, the increased intensity of the circular dichroism signals in the cis-1,3-DACH derivatives with respect to the analogous cis-(NH3)2 species could be a consequence of the greater bite angle of the cis-1,3-DACH carrier ligand with respect to cis-(NH3)2. Finally, the (cis-1,3-DACH)Pt(d(GpG)) adduct is present in two isomeric forms, each one giving a pair of H8 resonances linked by a NOE cross peak. The two isomers were formed in comparable amounts and had a dominance of the HH conformer but with some contribution of the ΔHT conformer which is related to the HH conformer by having the 3'-G base flipped with respect to the 5'-G residue.

The Influence of the Auxiliary Ligand in Monofunctional Pt(II) Anticancer Complexes on the DNA Backbone.

Monofunctional platinum complexes offer a promising alternative to cisplatin in cancer chemotherapy, showing a unique mechanism of action. Their ability to induce minor helix distortions effectively inhibits DNA transcription. In our study, we synthesized and characterized three monofunctional Pt(II) complexes with the general formula [Pt(en)(L)Cl]NO3, where en = ethylenediamine, and L = pyridine (py), 2-methylpyridine (2-mepy), and 2-phenylpyridine (2-phpy). The hydrolysis rates of [Pt(en)(py)Cl]NO3 (1) and [Pt(en)(2-mepy)Cl]NO3 (2) decrease with the bulkiness of the auxiliary ligand with k(1) = 2.28 ± 0.15 × 10-4 s-1 and k(2) = 8.69 ± 0.98 × 10-5 s-1 at 298 K. The complex [Pt(en)(2-phpy)Cl]Cl (3) demonstrated distinct behavior. Upon hydrolysis, an equilibrium (Keq = 0.385 mM) between the complexes [Pt(en)(2-phpy)Cl]+ and [Pt(en)(2-phpy-H+)]+ was observed with no evidence (NMR or HR-ESI-MS) for the presence of the aquated complex [Pt(en)(2-phpy)(H2O)]2+. Despite the kinetic similarities between phenanthriplatin and (2), complexes (1) and (2) exhibit minimal activity against A549 lung cancer cell line (IC50 > 100 µΜ), whereas complex (3) exhibits notable cytotoxicity (IC50 = 41.11 ± 2.1 µΜ). In examining the DNA binding of (1) and (2) to the DNA model guanosine (guo), we validated their binding through guoN7, which led to an increased population of the C3'-endo sugar conformation, as expected. However, we observed that the rapid transition 2E (C2'-endo) ↔ 3E (C3'-endo), in the case of [Pt(en)(py)(guo)](NO3)2 ([1-guo]), slows down in the case of [Pt(en)(2-mepy)(guo)](NO3)2 ([2-guo]), resulting in separate signals for the two conformers in the 1H NMR spectra. This phenomenon arises from the steric hindrance between the methyl group of pyridine and the sugar moiety of guanosine. Notably, this hindrance is absent in [2-(9-MeG)] (9-MeG = 9-methylguanine), probably due to the absence of a bulky sugar unit in 9-MeG. In the case of (3), where the bulkiness of the substitution on the pyridine is further increased by a phenyl group, we observed a notable proximity between 9-MeGH8 and the phenyl ring of 2-phpy. Considering that only (3) exhibited good cytotoxicity against the A549 cancer cell line, it is suggested that auxiliary ligands, L, with an extended aromatic system and proper orientation in complexes of the type cis-[Pt(en)(L)Cl]NO3, may enhance the cytotoxic activity of such complexes.

Combination of FOLFOXIRI Drugs with Oncolytic Coxsackie B3 Virus PD-H Synergistically Induces Oncolysis in the Refractory Colorectal Cancer Cell Line Colo320.

FOLFOXIRI chemotherapy is a first-line therapy for advanced or metastatic colorectal cancer (CRC), yet its therapeutic efficacy remains limited. Immunostimulatory therapies like oncolytic viruses can complement chemotherapies by fostering the infiltration of the tumor by immune cells and enhancing drug cytotoxicity. In this study, we explored the effect of combining the FOLFOXIRI chemotherapeutic agents with the oncolytic coxsackievirus B3 (CVB3) PD-H in the CRC cell line Colo320. Additionally, we examined the impact of the drugs on the expression of microRNAs (miRs), which could be used to increase the safety of oncolytic CVB3 containing corresponding miR target sites (miR-TS). The measurement of cytotoxic activity using the Chou-Talalay combination index approach revealed that PD-H synergistically enhanced the cytotoxic activity of oxaliplatin (OX), 5-fluorouracil (5-FU) and SN-38. PD-H replication was not affected by OX and SN-38 but inhibited by high concentrations of 5-FU. MiR expression levels were not or only slightly elevated by the drugs or with drug/PD-H combinations on Colo320 cells. Moreover, the drug treatment did not increase the mutation rate of the miR-TS inserted into the PD-H genome. The results demonstrate that the combination of FOLFOXIRI drugs and PD-H may be a promising approach to enhance the therapeutic effect of FOLFOXIRI therapy in CRC.

Biological Evaluation of Dinuclear Platinum(II) Complexes with Aromatic N-Heterocycles as Bridging Ligands.

The history of effective anti-cancer medications begins with the discovery of cisplatin's anti-cancer properties. Second-generation analogue, carboplatin, with a similar range of effectiveness, made progress in improving these drugs with fewer side effects and better solubility. Renewed interest in platinum-based drugs has been increasing in the past several years. These developments highlight a revitalized enthusiasm and ongoing exploration in platinum chemotherapy based on the series of dinuclear platinum(II) complexes, [{Pt(L)Cl}2(µ-bridging ligand)]2+, which have been synthesized and evaluated for their biological activities. These complexes are designed to target various cancerous conditions, exhibiting promising antitumor, antiproliferative, and apoptosis-inducing activities. The current work aims to shed light on the potential of these complexes as next-generation platinum-based therapies, highlighting their enhanced efficacy and reduced side effects, which could revolutionize the approach to chemotherapy.

Trans-[Pt(amine)Cl2(PPh3)] Complexes Target Mitochondria and Endoplasmic Reticulum in Gastric Cancer Cells.

Gastric cancer prognosis is still notably poor despite efforts made to improve diagnosis and treatment of the disease. Chemotherapy based on platinum agents is generally used, regardless of the fact that drug toxicity leads to limited clinical efficacy. In order to overcome these problems, our group has been working on the synthesis and study of trans platinum (II) complexes. Here, we explore the potential use of two phosphine-based agents with the general formula trans-[Pt(amine)Cl2(PPh3)], called P1 and P2 (with dimethylamine or isopropylamine, respectively). A cytotoxicity analysis showed that P1 and especially P2 decrease cell viability. Specifically, P2 exhibits higher activity than cisplatin in gastric cancer cells while its toxicity in healthy cells is slightly lower. Both complexes generate Reactive Oxygen Species, produce DNA damage and mitochondrial membrane depolarization, and finally lead to induced apoptosis. Thus, an intrinsic apoptotic pathway emerges as the main type of cell death through the activation of BAX/BAK and BIM and the degradation of MCL1. Additionally, we demonstrate here that P2 produces endoplasmic reticulum stress and activates the Unfolded Protein Response, which also relates to the impairment observed in autophagy markers such as p62 and LC3. Although further studies in other biological models are needed, these results report the biomolecular mechanism of action of these Pt(II)-phosphine prototypes, thus highlighting their potential as novel and effective therapies.

Erk Inhibition as a Promising Therapeutic Strategy for High IL-8-Secreting and Low SPTAN1-Expressing Colorectal Cancer.

Tumor recurrence and drug resistance are responsible for poor prognosis in colorectal cancer (CRC). DNA mismatch repair (MMR) deficiency or elevated interleukin-8 (IL-8) levels are characteristics of CRCs, which have been independently correlated with treatment resistance to common therapies. We recently demonstrated significantly impaired therapeutical response and increased IL-8 release of CRC cell lines with reduced expression of MMR protein MLH1 as well as cytoskeletal non-erythrocytic spectrin alpha II (SPTAN1). In the present study, decreased intratumoral MLH1 and SPTAN1 expression in CRCs could be significantly correlated with enhanced serum IL-8. Furthermore, using stably reduced SPTAN1-expressing SW480, SW620 or HT-29 cell lines, the RAS-mediated RAF/MEK/ERK pathway was analyzed. Here, a close connection between low SPTAN1 expression, increased IL-8 secretion, enhanced extracellular-signal-regulated kinase (ERK) phosphorylation and a mesenchymal phenotype were detected. The inhibition of ERK by U0126 led to a significant reduction in IL-8 secretion, and the combination therapy of U0126 with FOLFOX optimizes the response of corresponding cancer cell lines. Therefore, we hypothesize that the combination therapy of FOLFOX and U0126 may have great potential to improve drug efficacy on this subgroup of CRCs, showing decreased MLH1 and SPTAN1 accompanied with high serum IL-8 in affected patients.