Platinum-based Drugs Research Articles

Spliceosomal components‐mediated intercellular communication: role in chemoresistance acquisition of ovarian cancer cells

The relapse rate of ovarian cancer patients is about 85% with progression-free survival time less than two years. Cisplatin resistance of ovarian cancer cells cannot be explained only by mutations in DNA repair genes and increased expression of multidrug resistance proteins [Heijink et al., 2019]. It has been recently shown that cancer cells subjected to chemotherapy can secrete signaling molecules into the extracellular medium that contribute to the survival of neighboring tumor cells [Obenauf et al., 2015, Pavlyukov et al., 2018]. Thus, it is extremely important to take into account the role of intercellular signaling that occurs during therapy. In this study, we performed a comprehensive analysis of changes in secretomes of ovarian cancer cells under chemotherapy condition and demonstrated a new molecular mechanism for the acquisition of a more aggressive tumor phenotype. In addition to in vitro secretomes, we analyzed paired ascitic fluids from the same ovarian cancer patients before and after neoadjuvant chemotherapy (n = 10). We have shown that ascitic fluids after chemotherapy, as well as in vitro therapy-induced secretomes, contain components that contribute significantly to the formation of mesenchymal phenotype of primary cancer cell cultures, which was accompanied by increased migration and resistance to chemotherapy of intact tumor cells. Comprehensive proteomic analysis of secretomes and ascites revealed that extracellular fluids after chemotherapy are enriched with spliceosomal components. In addition, using fluorescence labelling and modified SILAC technology, we demonstrated the possibility of spliceosomal protein transport by extracellular vesicles from dying tumor cells to recipient cells. We suggest that splicing factors circulating in the extracellular space can “prepare” intact cancer cells for subsequent drug treatment. Therefore, combination of platinum-based drugs with spliceosomal inhibitors could improve the survival of patients with ovarian cancer.

Ruthenium(II)-curcumin liposome nanoparticles: Synthesis, characterization, and their effects against cervical cancer

Ruthenium complexes have increased the scope for improvement in current cancer treatment by replacing platinum-based drugs. However, to reduce metal-associated toxicity, a biocompatible flavonoid, such as curcumin, is indispensable, as it offers uncompensated therapeutic benefits through formation of complexes. In this study, we synthesized metal-based flavonoid complexes using ruthenium(II) and curcumin by adopting a convenient reflux reaction, represented as Ru-Cur complexes. These complexes were thoroughly characterized using 1H, 13C NMR, XPS, FT-IR, and UV–vis spectroscopy. As curcumin is sparingly soluble in water and has poor chemical stability, we loaded Ru-Cur complexes into liposomes and further formed nanoparticles (NPs) using the thin layer evaporation method. These were named Ru-Cur loaded liposome nanoparticles (RCLNPs). The effects of RCLNPs on cell proliferation was investigated using human cervical cancer cell lines (HeLa). These RCLNPs exhibited significant cytotoxicity in HeLa cells. The anticancer properties of RCLNPs were studied using reactive oxygen species (ROS), LDH, and MTT assays as well as live-dead staining. Nuclear damage studies of RCLNPs were performed in HeLa cells using the Hoechst staining assay.

Disulfide bond based cascade reduction-responsive Pt(IV) nanoassemblies for improved anti-tumor efficiency and biosafety

The platinum-based drugs prevail in the therapy of malignant tumors treatment. However, their clinical outcomes have been heavily restricted by severe systemic toxicities. To ensure biosafety and efficiency, herein, we constructed a disulfide bond inserted Pt(IV) self-assembled nanoplatform that is selectively activated by rich glutathione (GSH) in tumor site. Disulfide bond was introduced into the conjugates of oxaliplatin (IV) and oleic acid (OA) which conferred cascade reduction-responsiveness to nanoassemblies. Disulfide bond cleavage and reduction of Pt(IV) center occur sequentially as a cascade process. In comparison to oxaliplatin solution, Pt(IV) nanoparticles (NPs) achieved prolonged blood circulation and higher maximum tolerated doses. Furthermore, Oxa(IV)-SS-OA prodrug NPs exhibited potent anti-tumor efficiency against 4T1 cells and low toxicities in other normal tissues, which offers a promising nano-platform for potential clinical application.

Abstract IA-010: Deciphering DNA end resection at DSBs

Abstract Double stranded DNA break (DSB)s are repaired by two major mechanistically distinct pathways, homologous recombination (HR) and non-homologous end joining (NHEJ). A decisive factor in the choice between DSB repair pathways is in the competition between DNA end protection (necessary for NHEJ) and DNA end resection (necessary for HR). As the ‘master regulator’ of DSB repair pathway choice, 53BP1, a chromatin-associated reader of epigenetic marks at DSBs, helps channel DSBs into the NHEJ pathway by restricting BRCA1-dependent end resection. 53BP1 nucleates the assembly of a higher order ensemble that includes the Shieldin complex, CST complex, and DNA polymerase (Pol) a-primase complex. Loss of BRCA1 provides a therapeutic opportunity as these tumors are exquisitely sensitive to inhibitors of poly (ADP-ribose) polymerase (PARP), and are also susceptible to platinum-based drugs. Loss of 53BP1 or any of the 53BP1-interacting proteins restores end resection and causes PARPi resistance in BRCA1-mutant tumors. We recently identified Dynein light chain like protein 1 (DYNLL1) as as anti-resection factor. Loss of DYNLL1 allowed DNA end resection and restored HR, thereby inducing resistance to platinum drugs and PARPi in BRCA1-mutant tumors. At the molecular level, DYNLL1 limited the nucleolytic resection of DNA ends by interacting with the resection machinery. Importantly, purified DYNLL1 interacted with MRE11 and inhibited its exonuclease activity in vitro. Now we observe that 53BP1 loss prevents DYNLL1 recruitment to DSBs and more broadly to chromatin. We hypothesize that 53BP1 inhibits MRE11-mediated DNA end resection by recruiting DYNLL1 and that DYNLL1 functions in parallel of Shieldin-CST to regulate DNA end resection and DSB repair pathway choice. We are investigating the crosstalk between the Shieldin-CST and DYNLL1-MRE11 arms of the 53BP1-dependent anti-DNA end resection machinery. Citation Format: Dipanjan Chowdhury. Deciphering DNA end resection at DSBs [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-010.

Polyacrylic-conjugated polyamidoamine G4.0 dendrimer as a potential nanocarrier for effective delivery of cisplatin

Platinum complexes have paid much attention to develop new drugs for cancer therapy due to its inhibitory activity against cancerous cell growth. In the study, the strategically programming cationic PAMAM G4.0 with carboxylate motifs was introduced as a delivery platform for cisplatin. Partial amino groups on the surface of PAMAM G4.0 had coupled with active carboxylate groups on polyacrylic acid (PAA) in order to reduce the remaining problem of cationic dendrimer and improve delivery effectiveness of aquated cisplatin. Our results show that the full cationic PAMAM G4.0 was toxic against both breast cancer (MCF7) and human dermal fibroblast (HuDF) cell lines at 100 ppm concentration. In the contract, the PAA-conjugated PAMAM G4.0 significantly improved their cytocompatibility of the cationic dendrimer. In addition, the modified PAMAM dendrimers G4.0 showed high affinity with the aquated cisplatin due to the presence of abundant carboxylic groups. Notably, the aquated cisplatin-complexed PAA-G4.0 showed 2.94-folded reduction in the toxicity against NCI H460 in comparison to free cisplatin drugs. Hence, the G4.0-PAA/aquated cisplatin nano-complex may become a promising versatile strategy for improving antitumour efficacy and reducing the side effects of platinum-based drugs.

Anticancer Half-Sandwich Rhodium(III) Complexes

Platinum-based anticancer drugs are most likely the most successful group of bioinorganic compounds. Their apparent disadvantages have led to the development of anticancer compounds of other noble metals, resulting in several ruthenium-based drugs which have entered clinical trials on oncological patients. Besides ruthenium, numerous rhodium complexes have been recently reported as highly potent antiproliferative agents against various human cancer cells, making them potential alternatives to Pt- and Ru-based metallodrugs. In this review, half-sandwich Rh(III) complexes are overviewed. Many representatives show higher in vitro potency than and different mechanisms of action (MoA) from the conventional anticancer metallodrugs (cisplatin in most cases) or clinically studied Ru drug candidates. Furthermore, some of the reviewed Rh(III) arenyl complexes are also anticancer in vivo. Pioneer anticancer organorhodium compounds as well as the recent advances in the field are discussed properly, and adequate attention is paid to their anticancer activity, solution behaviour and various processes connected with their MoA. In summary, this work summarizes the types of compounds and the most important biological results obtained in the field of anticancer half-sandwich Rh complexes.

Immune checkpoint inhibitors for treatment of small-cell lung cancer: a systematic review and meta-analysis.

BackgroundSmall cell lung cancer (SCLC) is a very aggressive and proliferative disease, with little progress being having made for its treatment in decades. Our goal was to evaluate the effect of immune checkpoint inhibitors (ICIs) and identify optimal first-line interventions for the treatment of SCLC.MethodsA systematic literature search of the Cochrane Library, PubMed and oncology conference proceedings were conducted. Randomized trials evaluating ICIs for SCLC were included. We use the risk of bias tool in RevMan 5.3 to assess the quality of studies. We used Stata version 15.0 to carry out data direct comparison and R version 4.0.2 to conduct the Bayesian network analysis.ResultsA total of 16 relevant clinical trials comprising 4,476 patients were included. We found the magnitude of efficacy for ICIs as first-line therapy conferred a statistically significant benefit in overall survival (OS) and progression-free survival compared to chemotherapy alone. The results were 0.82 (95% CI, 0.76–0.89, P<0.001) and 0.80 (95% CI, 0.74–0.86, P<0.001). For objective response rate (ORR), the result (1.13, 95% CI, 0.97–1.31, P=0.109) was not significant. In the second-line and maintenance treatment, no additional benefit was observed. With regard to safety, results showed that for all grades of AEs and grades 3–4 AEs, the pooled results were 1.36 (95% CI: 0.50–3.70; P=0.543) and 1.35 (95% CI: 0.58–3.15; P=0.484) respectively. In addition, the indirect comparison results showed that nivolumab combined with chemotherapy led to the most significant improvement in OS, while durvalumab combined with chemotherapy was a more efficacious therapy for improving ORR compared with the other interventions; the probability were the best treatments was 73.93% and 81% respectively.DiscussionOur results showed ICIs combined with etoposide and platinum-based drugs as first-line treatment of SCLC have benefits for patients and there was no evidence of a significant difference in efficacy among the different ICI drugs used for the first-line therapy. As for toxicity, the ICIs did not increase the frequency AEs for patients. However, as some studies are ongoing and the full data have still not been reported, our conclusions may not be completely representative.

The Affinity of Carboplatin to B-Vitamins and Nucleobases.

Platinum compounds have found wide application in the treatment of various types of cancer and carboplatin is one of the main platinum-based drugs used as antitumor agents. The anticancer activity of carboplatin arises from interacting with DNA and inducing programmed cell death. However, such interactions may occur with other chemical compounds, such as vitamins containing aromatic rings with lone-pair orbitals, which reduces the anti-cancer effect of carboplatin. The most important aspect of the conducted research was related to the evaluation of carboplatin affinity to vitamins from the B group and the potential impact of such interactions on the reduction of therapeutic capabilities of carboplatin in anticancer therapy. Realized computations, including estimation of Gibbs Free Energies, allowed for the identification of the most reactive molecule, namely vitamin B6 (pyridoxal phosphate). In this case, the computational estimations indicating carboplatin reactivity were confirmed by spectrophotometric measurements.

Clinical and prognostic features of ovarian endometrioid carcinoma with synchronous endometrial lesions

Objective: To compare the clinical and prognostic characteristics of ovarian endometrioid carcinoma (OEC) patients with synchronous endometrial lesions and patients with pure OEC. Methods: A retrospective review of the medical records of patients received initial treatment and a postoperative pathological diagnosis of OEC at Peking University People's Hospital between August 1998 and December 2017 were performed. According to the inclusion criteria, a total of 56 patients with OEC were included in the study, including 13 patients concurrent with simultaneous endometrial lesions (Group A) and 43 patients with pure OEC (Group B). Results: Patients with synchronous endometrial lesions accounted for 23% (13/56). Mean age of Group A at diagnosis was (44.9±8.3) years old, 2/13 of patients were postmenopausal, and no one had a history of hypertension, the first symptom of 5/13 people was irregular vaginal bleeding. Mean age of Group B patients at diagnosis was (52.7±10.2) years old, 53% (23/43) of patients were postmenopausal, and 28% (12/43) patients had the history of hypertension, the first symptom of 4 (9%, 4/43) people was irregular vaginal bleeding. The differences of age, menopause status, history of hypertension and initial symptoms between the two groups were statistically significant (all P<0.05). There were no significant differences in fertility history, dysmenorrhea history, age of menarche, history of endometriosis, preoperative and postoperative CA125 level, International Federation of Gynecology and Obstetrics (FIGO) stage, tumor grade, metastatic site and platinum-based chemotherapy drug resistance between the two groups (all P>0.05). The overall 5-year survival rate of OEC patients was 91.6%, and the overall 5-year progression-free survival rate was 76.6%. Among them, the 5-year survival rate of the OEC concurrent with simultaneous endometrial lesions group was 80.2%, and the pure OEC group was 93.4%; the 5-year progression-free survival rate of the OEC concurrent with simultaneous endometrial lesions group was 74.1%, and the 5-year progression-free survival rate of the pure OEC group was 77.3%. There were no significant differences between the two groups (all P>0.05). Multivariate analysis showed that the independent factors for the prognosis of OEC patients were FIGO stage (P=0.006) and residual lesion size (P=0.020). Conclusions: OEC patients have a high proportion of simultaneous endometrial lesions. OEC with simultaneous endometrial lesions are younger than patients with pure OEC. Synchronous endometrial lesions do not affect the prognosis of patients with OEC.

Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy.

Cisplatin and other platinum-based chemotherapeutic drugs have been used extensively for the treatment of human cancers such as bladder, blood, breast, cervical, esophageal, head and neck, lung, ovarian, testicular cancers, and sarcoma. Cisplatin is commonly administered intravenously as a first-line chemotherapy for patients suffering from various malignancies. Upon absorption into the cancer cell, cisplatin interacts with cellular macromolecules and exerts its cytotoxic effects through a series of biochemical mechanisms by binding to Deoxyribonucleic acid (DNA) and forming intra-strand DNA adducts leading to the inhibition of DNA synthesis and cell growth. Its primary molecular mechanism of action has been associated with the induction of both intrinsic and extrinsic pathways of apoptosis resulting from the production of reactive oxygen species through lipid peroxidation, activation of various signal transduction pathways, induction of p53 signaling and cell cycle arrest, upregulation of pro-apoptotic genes/proteins, and down-regulation of proto-oncogenes and anti-apoptotic genes/proteins. Despite great clinical outcomes, many studies have reported substantial side effects associated with cisplatin monotherapy, while others have shown substantial drug resistance in some cancer patients. Hence, new formulations and several combinational therapies with other drugs have been tested for the purpose of improving the clinical utility of cisplatin. Therefore, this review provides a comprehensive understanding of its molecular mechanisms of action in cancer therapy and discusses the therapeutic approaches to overcome cisplatin resistance and side effects.

Gold Derivatives Development as Prospective Anticancer Drugs for Breast Cancer Treatment

Commonly used anticancer drugs are cisplatin and other platinum-based drugs. However, the use of these drugs in chemotherapy causes numerous side effects and the onset of frequent drug resistance phenomena. This review summarizes the most recent results on the gold derivatives used for their significant inhibitory effects on the in vitro proliferation of breast cancer cell models and for the consequences deriving from morphological changes in the same cells. In particular, the study discusses the antitumor activity of gold nanoparticles, gold (I) and (III) compounds, gold complexes and carbene-based gold complexes, compared with cisplatin. The results of screening studies of cytotoxicity and antitumor activity for the gold derivatives show that the death of cancer cells can occur intrinsically by apoptosis. Recent research has shown that gold (III) compounds with square planar geometries, such as that of cisplatin, can intercalate the DNA and provide novel anticancer agents. The gold derivatives described can make an important contribution to expanding the knowledge of medicinal bioorganometallic chemistry and broadening the range of anticancer agents available, offering improved characteristics, such as increased activity and/or selectivity, and paving the way for further discoveries and applications.

Single-Strand Annealing in Cancer.

DNA double-strand breaks (DSBs) are among the most serious forms of DNA damage. In humans, DSBs are repaired mainly by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Single-strand annealing (SSA), another DSB repair system, uses homologous repeats flanking a DSB to join DNA ends and is error-prone, as it removes DNA fragments between repeats along with one repeat. Many DNA deletions observed in cancer cells display homology at breakpoint junctions, suggesting the involvement of SSA. When multiple DSBs occur in different chromosomes, SSA may result in chromosomal translocations, essential in the pathogenesis of many cancers. Inhibition of RAD52 (RAD52 Homolog, DNA Repair Protein), the master regulator of SSA, results in decreased proliferation of BRCA1/2 (BRCA1/2 DNA Repair Associated)-deficient cells, occurring in many hereditary breast and ovarian cancer cases. Therefore, RAD52 may be targeted in synthetic lethality in cancer. SSA may modulate the response to platinum-based anticancer drugs and radiation. SSA may increase the efficacy of the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 (CRISPR associated 9) genome editing and reduce its off-target effect. Several basic problems associated with SSA, including its evolutionary role, interplay with HRR and NHEJ and should be addressed to better understand its role in cancer pathogenesis and therapy.

Half-Sandwich Ru(p-cymene) Compounds with Diphosphanes: In Vitro and In Vivo Evaluation As Potential Anticancer Metallodrugs.

Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl][CF3SO3] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, 1H and 31P{1H} NMR, UV-vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC50 values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC50 value about 1 order of magnitude higher than any IC50 concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy.

Monofunctional Platinum(II) Anticancer Agents.

Platinum-based anticancer drugs represented by cisplatin play important roles in the treatment of various solid tumors. However, their applications are largely compromised by drug resistance and side effects. Much effort has been made to circumvent the drug resistance and general toxicity of these drugs. Among multifarious designs, monofunctional platinum(II) complexes with a general formula of [Pt(3A)Cl]+ (A: Ammonia or amine) stand out as a class of “non-traditional” anticancer agents hopeful to overcome the defects of current platinum drugs. This review aims to summarize the development of monofunctional platinum(II) complexes in recent years. They are classified into four categories: fluorescent complexes, photoactive complexes, targeted complexes, and miscellaneous complexes. The intention behind the designs is either to visualize the cellular distribution, or to reduce the side effects, or to improve the tumor selectivity, or inhibit the cancer cells through non-DNA targets. The information provided by this review may inspire researchers to conceive more innovative complexes with potent efficacy to shake off the drawbacks of platinum anticancer drugs.

DOCK4 Is a Platinum-Chemosensitive and Prognostic-Related Biomarker in Ovarian Cancer.

Ovarian carcinoma (OV) is a lethal gynecological malignancy. Most OV patients develop resistance to platinum-based chemotherapy and recurrence. Peroxisome proliferator-activated receptors (PPARs) are the ligand activating transcription factor of the nuclear receptor superfamily. PPARs as important transcriptional regulators regulate important physiological processes such as lipid metabolism, inflammation, and wound healing. Several reports point out that PPARs can also have an effect on the sensitivity of tumor cells to platinum-based chemotherapy drugs. However, the role of PPAR-target related genes (PPAR-TRGs) in chemotherapeutic resistance of OV remains unclear. The present study is aimed at optimizing candidate genes by integrating platinum-chemotherapy expression data and PPAR family genes with their targets. The gene expression profiles were obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database. A total of 4 genes (AP2A2, DOCK4, HSDL2, and PDK4) were the candidate differentially expressed genes (DEGs) of PPAR-TRGs with platinum chemosensitivity. After conducting numerous survival analyses using different cohorts, we found that only the upexpression of DOCK4 has important significance with the poor prognosis of OV patients. Meanwhile, DOCK4 is detected in plasma and enriched in neutrophil and monocyte cells of the blood. We further found that there were significant correlations between DOCK4 expression and the levels of CD4+ T cell infiltration, dendritic cell infiltration, and neutrophil infiltration in OV. In addition, we verified the expression level of DOCK4 in OV cell lines treated with platinum drugs and found that DOCK4 is potentially responsive to platinum drugs. In conclusion, DOCK4 is potentially associated with immune cell infiltration and represents a valuable prognostic biomarker in ovarian cancer patients.

Epigenetics/Epigenomics and Prevention of Early Stages of Cancer by Isothiocyanates.

Cancer is a complex disease and cancer development takes 10-50 years involving epigenetics. Evidence suggests that approximately 80% of human cancers are linked to environmental factors impinging upon genetics/epigenetics. Because advanced metastasized cancers are resistant to radiotherapy/chemotherapeutic drugs, cancer prevention by relatively nontoxic chemopreventive "epigenetic modifiers" involving epigenetics/epigenomics is logical. Isothiocyanates are relatively nontoxic at low nutritional and even higher pharmacologic doses, with good oral bioavailability, potent antioxidative stress/antiinflammatory activities, possess epigenetic-modifying properties, great anticancer efficacy in many in vitro cell culture and in vivo animal models. This review summarizes the latest advances on the role of epigenetics/epigenomics by isothiocyanates in prevention of skin, colon, lung, breast, and prostate cancers. The exact molecular mechanism how isothiocyanates modify the epigenetic/epigenomic machinery is unclear. We postulate "redox" processes would play important roles. In addition, isothiocyanates sulforaphane and phenethyl isothiocyanate, possess multifaceted molecular mechanisms would be considered as "general" cancer preventive agents not unlike chemotherapeutic agents like platinum-based or taxane-based drugs. Analogous to chemotherapeutic agents, the isothiocyanates would need to be used in combination with other nontoxic chemopreventive phytochemicals or drugs such as NSAIDs, 5-α-reductase/aromatase inhibitors targeting different signaling pathways would be logical for the prevention of progression of tumors to late advanced metastatic states.

Exploring the clinical value of tumor microenvironment in platinum-resistant ovarian cancer.

Platinum resistance in epithelial ovarian cancer (OvCa) is rising at an alarming rate, with recurrence of chemo-resistant high grade serous OvCa (HGSC) in roughly 75 % of all patients. Additionally, HGSC has an abysmal five-year survival rate, standing at 39 % and 17 % for FIGO stages III and IV, respectively. Herein we review the crucial cellular interactions between HGSC cells and the cellular and non-cellular components of the unique peritoneal tumor microenvironment (TME). We highlight the role of the extracellular matrix (ECM), ascitic fluid as well as the mesothelial cells, tumor associated macrophages, neutrophils, adipocytes and fibroblasts in platinum-resistance. Moreover, we underscore the importance of other immune-cell players in conferring resistance, including natural killer cells, myeloid-derived suppressive cells (MDSCs) and T-regulatory cells. We show the clinical relevance of the key platinum-resistant markers and their correlation with the major pathways perturbed in OvCa. In parallel, we discuss the effect of immunotherapies in re-sensitizing platinum-resistant patients to platinum-based drugs. Through detailed analysis of platinum-resistance in HGSC, we hope to advance the development of more effective therapy options for this aggressive disease.

New combination chemotherapy of cisplatin with an electron-donating compound for treatment of multiple cancers

Cisplatin is the first and most widely used platinum-based chemotherapy drug and is the cornerstone agent in treating a broad spectrum of cancers. However, its clinical application is often limited by severe toxic side effects and drug resistance. Based on the discovered dissociative electron transfer mechanism of cisplatin, a novel combination of cisplatin with [9-(2-carboxyphenyl)-6-diethylamino-3-xanthenylidene]-diethylammonium chloride (basic violet 10, BV10) is proposed to potentiate the chemotherapeutic effect of cisplatin. Here, we show that this combination enhances the anti-cancer effect of cisplatin in both in vitro cell lines and in vivo xenograft mouse models of cisplatin-sensitive and -resistant lung, ovarian and cervical cancers while introducing minimal additional toxic side effects. Furthermore, femtosecond time-resolved laser spectroscopic measurements demonstrate that cisplatin reacts with BV10 via an electron transfer mechanism. These results indicate that the combination of cisplatin with BV10 is promising for improving the chemotherapy of cancers with various extents of cisplatin resistance.

Enhancing the activity of platinum-based drugs by improved inhibitors of ERCC1-XPF-mediated DNA repair.

The ERCC1-XPF 5'-3' DNA endonuclease complex is involved in the nucleotide excision repair pathway and in the DNA inter-strand crosslink repair pathway, two key mechanisms modulating the activity of chemotherapeutic alkylating agents in cancer cells. Inhibitors of the interaction between ERCC1 and XPF can be used to sensitize cancer cells to such drugs. We tested recently synthesized new generation inhibitors of this interaction and evaluated their capacity to sensitize cancer cells to the genotoxic activity of agents in synergy studies, as well as their capacity to inhibit the protein-protein interaction in cancer cells using proximity ligation assay. Compound B9 showed the best activity being synergistic with cisplatin and mitomycin C in both colon and lung cancer cells. Also, B9 abolished the interaction between ERCC1 and XPF in cancer cells as shown by proximity ligation assay. Results of different compounds correlated with values from our previously obtained in silico predictions. Our results confirm the feasibility of the approach of targeting the protein-protein interaction between ERCC1 and XPF to sensitize cancer cells to alkylating agents, thanks to the improved binding affinity of the newly synthesized compounds.

Bioaccumulation and toxicity of oxaliplatin in fresh water: A study with Lemna minor

Oxaliplatin is the newest platinum-based drug to be used widely in chemotherapy. However, very little is known about its behaviour and toxicity once discharged to the environment. In this study, the freshwater macrophyte, Lemna minor, has been exposed to three concentrations of the drug (low, medium and high; 0.4, 10 and 100 μg mL−1, respectively) for seven days according to OECD guidelines and the growth rate, biochemical changes and extent of membrane damage determined. The stability of oxaliplatin was also monitored during the exposures and the accumulation, as both adsorbed and internalised fractions, evaluated by chemical extraction and digestion at the end of the experiment. Oxaliplatin appeared to remain intact throughout, with no measurable metabolite formation in the growth medium, and bioconcentration factors were < 100 mL g−1. The majority of oxaliplatin taken up by L. minor (about 66 to 84%) was internalised, presumably through passive diffusion and, possibly, uptake through transporters. Among the end-points tested, only relative growth rate of frond area and ion leakage were adversely affected at the medium and/or high concentrations employed. These observations suggest that oxaliplatin is unlikely to be phytotoxic at concentrations typically encountered in the environment and that L. minor is not a suitable biomonitor or phytoremediator of contaminated waters.