Anticancer Activity Of Cisplatin Research Articles

Bacterial DnaK reduces the activity of anti-cancer drugs cisplatin and 5FU

BackgroundChemotherapy is a primary treatment for cancer, but its efficacy is often limited by cancer-associated bacteria (CAB) that impair tumor suppressor functions. Our previous research found that Mycoplasma fermentans DnaK, a chaperone protein, impairs p53 activities, which are essential for most anti-cancer chemotherapeutic responses.MethodsTo investigate the role of DnaK in chemotherapy, we treated cancer cell lines with M. fermentans DnaK and then with commonly used p53-dependent anti-cancer drugs (cisplatin and 5FU). We evaluated the cells’ survival in the presence or absence of a DnaK-binding peptide (ARV-1502). We also validated our findings using primary tumor cells from a novel DnaK knock-in mouse model. To provide a broader context for the clinical significance of these findings, we investigated human primary cancer sequencing datasets from The Cancer Genome Atlas (TCGA). We identified F. nucleatum as a CAB carrying DnaK with an amino acid composition highly similar to M. fermentans DnaK. Therefore, we investigated the effect of F. nucleatum DnaK on the anti-cancer activity of cisplatin and 5FU.ResultsOur results show that both M. fermentans and F. nucleatum DnaKs reduce the effectiveness of cisplatin and 5FU. However, the use of ARV-1502 effectively restored the drugs' anti-cancer efficacy.ConclusionsOur findings offer a practical framework for designing and implementing novel personalized anti-cancer strategies by targeting specific bacterial DnaKs in patients with poor response to chemotherapy, underscoring the potential for microbiome-based personalized cancer therapies.

Ameliorative effect of zinc oxide-chitosan conjugates on the anticancer activity of cisplatin: Approach for breast cancer treatment

Breast cancer is the second most prevalent cancer affecting both males and females, comprising nearly 30 % of all cancer cases. While chemotherapeutic agents, such as cisplatin (Cis), have proven successful in cancer treatment, concerns persist regarding their efficacy and the potentially dangerous side effects. Consequently, there is a crucial and ongoing need to develop approaches that minimize side effects associated with chemotherapy. In the present work, various types of nanoparticles (NPs) were synthesized and loaded with Cis. Cis was conjugated with nanocarriers such as zinc oxide (ZnO), ZnO modified with mandelic acid and graphene oxide (GO), chitosan (CS), and CS modified with ZnO and GO to enhance the selectivity of Cis towards cancer cells. Zeta potentials and particles size were assessed using electrophoretic light scattering and dynamic light scattering. NPs were characterized using transmission electron microscopy, Fourier-transform infrared spectroscopy, and X-ray diffraction. The impact of standalone Cis as well as its nanoconjugated form on the behavior of MCF-7 cell line was investigated using WST-1 cell proliferation and apoptosis/necrosis assays. Experimental findings revealed that among the various NPs tested, ZnO, and CS NPs exhibited the highest loading percentage of Cis, surpassing the loading percentages achieved with other NPs. Cytotoxicity assay showed the enhanced effect of Cis when conjugated with ZnO and CS NPs. Flow cytometry-based assays and confocal microscopy confirmed that ZnO/Cis and CS/Cis induced apoptosis. The cisplatin-nanocomplex exhibited a descending order of early apoptosis and late apoptosis in the following order: ZnO, Cis, CS, ZnO-M, CS-GO, ZnO-GO, CS-ZnO, and CS-ZnO, Cis, CS, CS-GO, ZnO-M, ZnO, ZnO-GO, respectively. None of the nanoparticle complexes displayed a significant percentage of necrotic cells, with the highest percentage reaching 4.65 % in the case of CS-GO/Cis.

Short-term autophagy inhibition by autophinib or SAR405 does not alter the effect of cisplatin on ATP production in prostate cancer cells.

Cisplatin is a widely used anticancer drug for the treatment of many solid cancers. DNA damage is thought to be the key mechanism of cisplatin's anticancer activity. However, cisplatin may also affect cellular metabolism. The aim of this study was to determine the effect of cisplatin on the types of ATP production (OXPHOS versus glycolysis) and their rate in prostate cancer cells and to determine the potentially protective effect of autophagy and amino acids during cisplatin treatment. We also wanted to investigate the potential synergy between the metabolic effects of cisplatin on ATP production and the inhibition of autophagy. Cisplatin treatment can significantly affect the metabolism of cancer cells. Important metabolic pathways can be altered, leading to changes in energy production and nutrient utilization. Autophagy and amino acid pool modulations can serve as protective mechanisms significantly affecting tumor cell survival under metabolic stress caused by anticancer treatment. By enabling the recycling of amino acids, autophagy helps cancer cells maintain cellular homeostasis and overcome nutrient limitations. Thus, inhibition of autophagy could have a supportive effect on the metabolic effects of cisplatin. After cisplatin treatment, ATP production by way of OXPHOS was significantly decreased in 22Rv1 and PC-3 cells. On the other hand, ATP production by glycolysis was not significantly affected in 22Rv1 cells. DU145 cells with dysfunctional autophagy were the most sensitive to cisplatin treatment and showed the lowest ATP production. However, short-term autophagy inhibition (24h) by autophinib or SAR405 in 22Rv1 and PC-3 cells did not alter the effect of cisplatin on ATP production. Levels of some amino acids (arginine, methionine) significantly affected the fitness of cancer cells. Persistent defects of autophagy can affect the metabolic sensitivity of cancer cells due to interference with arginine metabolism. Amino acids contained in the culture medium had an impact on the overall effect of cisplatin (Fig. 3, Ref. 38).

One-year reductions in cisplatin-related chronic kidney disease (CKD) in patients with head and neck (HNC) cancer treated with avasopasem manganese: A prespecified analysis from the phase 3 ROMAN trial.

6066 Background: Cisplatin-induced acute kidney injury (AKI), acute kidney disease (AKD), and chronic kidney disease (CKD) are associated with increased production of reactive oxygen species, notably superoxide, in conjunction with alterations in mitochondrial electron transport chain complex activities in tubular epithelial cells (Mapuskar et al. Antioxidants 2021;10:1329). These pathologies can be targeted and thereby inhibited by increasing superoxide dismutase activity, which converts superoxide to hydrogen peroxide. The investigational new drug avasopasem manganese (AVA), a selective dismutase mimetic, ameliorated cisplatin-induced kidney injury in mice (Mapuskar et al. Redox Biol 2019;20:98). Preclinical results also demonstrate that AVA does not interfere with cisplatin anticancer activity (Mohanty et al. Cancer Res 2018;78[13_suppl]:Abstract 2929). Consistent with this, a retrospective analysis of 1- and 2-year kidney function of a limited subset of patients treated in a randomized, placebo (PBO)-controlled phase 2b trial of AVA to reduce severe oral mucositis (SOM) from radiotherapy and cisplatin (CRT) suggested that AVA prevented or reduced cisplatin-related CKD compared to PBO (Steinbach et al. J Clin Oncol 2020;38[15_suppl]:Abstract 12071). Methods: The ROMAN phase 3 trial (NCT03689712; ITT n = 407) of CRT in combination with AVA or PBO demonstrated improved incidence, duration, and onset of SOM by AVA (n = 241) vs PBO (n = 166) (Anderson et al. J Clin Oncol 2022;40[16_suppl]:Abstract 6005). In ROMAN, prospectively defined follow-up of serum creatinine (sCr) and estimated glomerular filtration rates (eGFR) were assessed every 3 months for 1 year following 7 weeks of CRT. Results: At 1-year follow-up, AVA was associated with significant improvements in preservation of eGFR ( P= 0.0008) and sCr ( P= 0.006) levels vs PBO. Grade 3+ CKD (eGFR < 60 mL/min) results through 12 months show 10% AVA vs 20% PBO (relative risk 0.55, P= 0.0043). Regarding cisplatin schedule, patients receiving Q3W therapy show grade 3+ CKD of 12% AVA vs 22% PBO; patients receiving QW therapy show AVA 9% vs PBO 19%. During treatment, nominal reduction of the incidence of AKI adverse events (0.8% AVA vs 3.6% PBO) was also observed. Conclusions: At 1-year follow-up, AVA appears to reduce cisplatin-related CKD in the study population and may also reduce cisplatin-related AKI during treatment. These results carry significance beyond CRT for HNC, potentially impacting platinum-containing regimens in other cancers. Clinical trial information: NCT03689712 .

Recent Advances and Therapeutic Journey of Schiff Base Complexes with Selected Metals (Pt, Pd, Ag, Au) as Potent Anticancer Agents: A Review.

Schiff bases and their transition metal complexes play an important role in the field of medicine, in particular in the treatment of cancer. Since the discovery of the cisplatin anticancer activity, great efforts have focused on the rational design of metal-based anticancer drugs that can be potentially used for the treatment of cancer. However, drug resistance and significant side effects greatly limit its clinical application. This has inspired medicinal chemists to employ various strategies in the development of novel and effective anticancer drugs. Recently, a greater number of transition metal complexes have been designed and evaluated for their anticancer activities, and some of them were at different stages of clinical studies. Amongst these, platinum, palladium, gold and silver complexes have an important place within medicinal and inorganic chemistry. This review article discusses Schiff bases and their complexes with selected transition metals (Pd, Pt, Ag, Au) for anticancer activity against different cancer cell lines.

Pro-Inflammatory Signalling PRRopels Cisplatin-Induced Toxicity.

Cisplatin is a platinum-based chemotherapeutic that has long since been effective against a variety of solid-cancers, substantially improving the five-year survival rates for cancer patients. Its use has also historically been limited by its adverse drug reactions, or cisplatin-induced toxicities (CITs). Of these reactions, cisplatin-induced nephrotoxicity (CIN), cisplatin-induced peripheral neuropathy (CIPN), and cisplatin-induced ototoxicity (CIO) are the three most common of several CITs recognised thus far. While the anti-cancer activity of cisplatin is well understood, the mechanisms driving its toxicities have only begun to be defined. Most of the literature pertains to damage caused by oxidative stress that occurs downstream of cisplatin treatment, but recent evidence suggests that the instigator of CIT development is inflammation. Cisplatin has been shown to induce pro-inflammatory signalling in CIN, CIPN, and CIO, all of which are associated with persisting markers of inflammation, particularly from the innate immune system. This review covered the hallmarks of inflammation common and distinct between different CITs, the role of innate immune components in development of CITs, as well as current treatments targeting pro-inflammatory signalling pathways to conserve the use of cisplatin in chemotherapy and improve long-term health outcomes of cancer patients.

The Rationale for "Laser-Induced Thermal Therapy (LITT) and Intratumoral Cisplatin" Approach for Cancer Treatment.

Cisplatin is one of the most widely used anticancer drugs in the treatment of various types of solid human cancers, as well as germ cell tumors, sarcomas, and lymphomas. Strong evidence from research has demonstrated higher efficacy of a combination of cisplatin and derivatives, together with hyperthermia and light, in overcoming drug resistance and improving tumoricidal efficacy. It is well known that the antioncogenic potential of CDDP is markedly enhanced by hyperthermia compared to drug treatment alone. However, more recently, accelerators of high energy particles, such as synchrotrons, have been used to produce powerful and monochromatizable radiation to induce an Auger electron cascade in cis-platinum molecules. This is the concept that makes photoactivation of cis-platinum theoretically possible. Both heat and light increase cisplatin anticancer activity via multiple mechanisms, generating DNA lesions by interacting with purine bases in DNA followed by activation of several signal transduction pathways which finally lead to apoptosis. For the past twenty-seven years, our group has developed infrared photo-thermal activation of cisplatin for cancer treatment from bench to bedside. The future development of photoactivatable prodrugs of platinum-based agents injected intratumorally will increase selectivity, lower toxicity and increase efficacy of this important class of antitumor drugs, particularly when treating tumors accessible to laser-based fiber-optic devices, as in head and neck cancer. In this article, the mechanistic rationale of combined intratumor injections of cisplatin and laser-induced thermal therapy (CDDP–LITT) and the clinical application of such minimally invasive treatment for cancer are reviewed.

Supramolecular self-associating amphiphiles (SSAs) as nanoscale enhancers of cisplatin anticancer activity.

Many chemotherapeutic drugs have a narrow therapeutic window due to inefficient tumour cell permeation. Supramolecular self-associating amphiphilic salts (SSAs) are a unique class of small molecules that offer potential as next generation cancer drugs and/or therapeutic enhancement agents. Herein, we demonstrate the cytotoxicity of seven SSAs towards both ovarian and glioblastoma cancer cells. We also utilize the intrinsic fluorescent properties of one of these lead SSAs to provide evidence for this class of compound to both bind to the exterior cancer cell surface and permeate the cell membrane, to become internalized. Furthermore, we demonstrate synergistic effects of two lead SSAs on cisplatin-mediated cytotoxicity of ovarian cancer cells and show that this correlates with increased DNA damage and apoptosis versus either agent alone. This work provides the first evidence that SSAs interact with and permeate cancer cell membranes and enhance the cytotoxic activity of a chemotherapeutic drug in human cancer cells.

Dibenzazepine Attenuates Against Cisplatin-Induced Nephrotoxicity in Rats: Involvement of NOTCH Pathway.

Cisplatin is one of the standard anti-cancer agents that are used to treat variety of solid tumors. Nevertheless, due to the accumulation of cisplatin in the renal epithelial cells, nephrotoxicity was found to be the main side effect that limits its clinical use. The current study was conducted to assess the potential nephroprotective effect of dibenzazepine, a Notch inhibitor, against cisplatin-induced nephrotoxicity in rats as well as the possible mechanisms underlying this nephroprotection. The rats were pre-treated with 2 mg/kg dibenzazepine for 7 days before giving a single nephrotoxic dose of cisplatin (7 mg/kg). Cisplatin induced acute nephrotoxicity, where blood urea nitrogen and serum creatinine levels were significantly increased. Besides, lipid peroxidation was markedly elevated and the levels of reduced glutathione and catalase were significantly reduced. Also, the tissue levels of the pro-inflammatory mediators; IL-1β, TNF-α, and NF-kB, were significantly increased in the cisplatin group. The pre-treatment with dibenzazepine significantly mitigated the nephrotoxic effects of cisplatin, the oxidative stress and inflammatory status as well as decreased caspase-3 expression, as compared to the cisplatin group. Furthermore, the up-regulation of Notch-1 and Hes-1 was found to be involved in cisplatin-induced nephrotoxicity and their expression was significantly reduced by dibenzazepine. The nephroprotective effect of dibenzazepine was further confirmed by the histopathological assessment. Moreover, dibenzazepine pre-treatment of hela and PC3 cells in vitro did not antagonize the cisplatin anti-cancer activity. In conclusion, these findings show that dibenzazepine provides protection against cisplatin-induced nephrotoxicity. Moreover, the up-regulation of the Notch pathway was shown to play a role in the pathogenesis of cisplatin-induced renal injury.

Germacrone Reduces Cisplatin-Induced Toxicity of Renal Proximal Tubular Cells via Inhibition of Organic Cation Transporter.

Cisplatin is a widely used chemotherapy for solid tumors; however, its benefits are limited by serious nephrotoxicity, particularly in proximal tubular cells. The present study investigated the renoprotective effect and mechanisms of germacrone, a bioactive terpenoid compound found in Curcuma species on cisplatin-induced toxicity of renal cells. Germacrone (50 and 100 µM) attenuated apoptosis of human renal proximal tubular cells, RPTEC/TERT1 following treatment with 50 µM cisplatin and for 48 h. Co-treating RPTEC/TERT1 cells with cisplatin and germacrone significantly reduced cellular platinum content compared with cisplatin treatment alone. The effect of germacrone on organic cation transporter 2 (OCT2) which is a transporter responsible for cisplatin uptake was determined. Germacrone showed an inhibitory effect on OCT2-mediated methyl-4-phenylpyridinium acetate (3H-MPP+) uptake with IC50 of 15 µM with less effect on OCT1. The germacrone's protective effect on cisplatin-induced cytotoxicity was not observed in cancer cells; cisplatin's anti-cancer activity was preserved. In conclusion, germacrone prevents cisplatin-induced toxicity in renal proximal tubular cells via inhibition OCT2 transport function and reducing cisplatin accumulation. Thus germacrone may be a good candidate agent used for reducing cisplatin-induced nephrotoxicity.

RIP1 promotes proliferation through G2/M checkpoint progression and mediates cisplatin-induced apoptosis and necroptosis in human ovarian cancer cells.

Receptor-interacting protein 1 (RIP1, also known as RIPK1) is not only a tumor-promoting factor in several cancers but also mediates either apoptosis or necroptosis in certain circumstances. In this study we investigated what role RIP1 plays in human ovarian cancer cells. We showed that knockout (KO) of RIP1 substantially suppressed cell proliferation, accompanied by the G2/M checkpoint arrest in two human ovarian cancer cell lines SKOV3 and A2780. On the other hand, RIP1 KO remarkably attenuated cisplatin-induced cytotoxicity, which was associated with reduction of the apoptosis markers PARP cleavage and the necroptosis marker phospho-MLKL. We found that RIP1 KO suppressed cisplatin-induced ROS accumulation in both SKOV3 and A2780 cells. ROS scavenger BHA, apoptosis inhibitor Z-VAD or necroptosis inhibitor NSA could effectively suppress cisplatin’s cytotoxicity in the control cells, suggesting that ROS-mediated apoptosis and necroptosis were involved in cisplatin-induced cell death. In addition, blocking necroptosis with MLKL siRNA effectively attenuated cisplatin-induced cytotoxicity. In human ovarian cancer A2780 cell line xenograft nude mice, RIP1 KO not only significantly suppressed the tumor growth but also greatly attenuated cisplatin’s anticancer activity. Our results demonstrate a dual role of RIP1 in human ovarian cancer: it acts as either a tumor-promoting factor to promote cancer cell proliferation or a tumor-suppressing factor to facilitate anticancer effects of chemotherapeutics such as cisplatin.

Simple Trans-Platinum Complex Bearing 3-Aminoflavone Ligand Could Be a Useful Drug: Structure-Activity Relationship of Platinum Complex in Comparison with Cisplatin.

Following previous studies devoted to trans–Pt(3-af)2Cl2, in this paper, the molecular structure and intermolecular interactions of the title complex are compared with other cisplatin analogues of which the crystal structures are presented in the Cambridge Structural Database (CSD). Molecular Hirshfeld surface analysis and computational methods were used to examine a possible relationship between the structure and anticancer activity of trans–Pt(3-af)2Cl2. The purpose of the article was also to investigate the effect of hyperthermia on the anticancer activity of cisplatin, cytostatics used in the treatment of patients with ovarian cancer and a new analogue of cisplatin-trans–Pt(3-af)2Cl2. The study was conducted on two cell lines of ovarian cancer sensitive to Caov-3 cytostatics and the OVCAR-3 resistant cisplatin line. The study used the MTT (3-(4,5-dimethylthiazol-2,5-diphenyltetrazolium bromide) cell viability assay, LDH (lactate dehydrogenase), and the quantitative evaluation method for measuring gene expression, i.e., qPCR with TagMan probes. Reduced survivability of OVCAR-3 and Caov-3 cells exposed to cytostatics at elevated temperatures (37 °C, 40 °C, 43 °C) was observed. Hyperthermia may increase the sensitivity of cells to platinum-based antineoplastic drugs and paclitaxel, which may be associated with the reduction of gene expression related to apoptotic processes.

Effects of silymarin-loaded amphiphilic chitosan polymeric micelles on the renal toxicity and anticancer activity of cisplatin

This research aimed to evaluate the effects of silymarin (SM)-loaded polymeric micelles (PMs) on the renal toxicity and anticancer activity of cisplatin. Amphiphilic chitosan derivatives were employed to develop SM-loaded PMs. The permeation across an intestinal membrane, cytotoxicity, and renal toxicity of cisplatin during the treatment were evaluated. The SM-loaded PMs had small particle sizes (326–336 nm), negative surface charge, high entrapment efficiency (47–70%), and demonstrated pH-sensitive release. Rapid drug release was obtained at pH 7.4 (81–87% in 4 h). The SM-loaded PMs exhibited higher flux than free SM. Moreover, the pretreatment of SM (50–100 μg/mL)-loaded PMs increased the killing efficacy of cisplatin on the cancer cells. The renoprotective effect was witnessed (p < 0.05) on the cells pretreated with SM-loaded benzyl-functionalized succinyl chitosan (BSC) PMs compared with those treated with only cisplatin, which the % cell viability increased from 29% to 82% and 96% for the PMs with SM concentration of 50 and 100 μg/mL, respectively. Moreover, the reduction in cell apoptosis and necrosis induced by cisplatin has been observed. In conclusion, SM-loaded BSC PMs could improve the bioavailability of SM, enhance the therapeutic effect, and protect renal damage during the treatment with cisplatin.

Gallic acid has anticancer activity and enhances the anticancer effects of cisplatin in non‑small cell lung cancer A549 cells via the JAK/STAT3 signaling pathway.

Gallic acid (3,4,5‑trihydroxybenzoic acid; GA), a plant‑derived natural phenolic compound, has been reported to prevent the development and progression of various types of cancers. However, there has been little elaboration of the anticancer effects and underlying mechanisms of GA alone and/or in combination with cisplatin in non‑small cell lung cancer (NSCLC). The aim of the present study was to investigate the anticancer effects of GA on NSCLC A549 cells and its auxiliary effects on the anticancer activity of cisplatin. The results revealed that GA inhibited the proliferation and induced the apoptosis of NSCLC A549 cells in dose‑ and time‑dependent manners, which was associated with upregulated B‑cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax) and downregulated Bcl‑2. Notably, the results also indicated that GA enhanced the anticancer effects of cisplatin in the inhibition of cancer cell proliferation and the induction of cell apoptosis following elevated Bax expression and suppressed Bcl‑2 expression. Furthermore, the results of the present study also demonstrated that GA exerted independent anticancer effects on NSCLC A549 cells, and facilitated the anticancer effects of cisplatin by modulating the JAK/STAT3 signaling pathway and downstream apoptotic molecules. These results may serve as a rationale for further basic studies and preclinical investigations on the anticancer effects of GA and its auxiliary effects on cisplatin function in human NSCLC.

Effects of antidiabetic drug on the anticancer activity of Cisplatin

Effects of antidiabetic drug on the anticancer activity of Cisplatin

Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC

IntroductionWe hypothesized that activating KRAS mutations and inactivation of the liver kinase B1 (LKB1) oncosuppressor can cooperate to sustain NSCLC aggressiveness. We also hypothesized that the growth advantage of KRAS/LKB1 co-mutated tumors could be balanced by higher sensitivity to metabolic stress conditions, such as metformin treatment, thus revealing new strategies to target this aggressive NSCLC subtype. MethodsWe retrospectively determined the frequency and prognostic value of KRAS/LKB1 co-mutations in tissue specimens from NSCLC patients enrolled in the TAILOR trial. We generated stable LKB1 knockdown and LKB1-overexpressing isogenic H1299 and A549 cell variants, respectively, to test the in vitro efficacy of metformin. We also investigated the effect of metformin on cisplatin-resistant CD133+ cells in NSCLC patient-derived xenografts. ResultsWe found a trend towards worse overall survival in patients with KRAS/LKB1 co-mutated tumors as compared to KRAS-mutated ones (hazard ratio: 2.02, 95% confidence interval: 0.94–4.35, p = 0.072). In preclinical experiments, metformin produced pro-apoptotic effects and enhanced cisplatin anticancer activity specifically in KRAS/LKB1 co-mutated patient-derived xenografts. Moreover, metformin prevented the development of acquired tumor resistance to 5 consecutive cycles of cisplatin treatment (75% response rate with metformin-cisplatin as compared to 0% response rate with cisplatin), while reducing CD133+ cells. ConclusionsLKB1 mutations, especially when combined with KRAS mutations, may define a specific and more aggressive NSCLC subtype. Metformin synergizes with cisplatin against KRAS/LKB1 co-mutated tumors, and may prevent or delay the onset of resistance to cisplatin by targeting CD133+ cancer stem cells. This study lays the foundations for combining metformin with standard platinum-based chemotherapy in the treatment of KRAS/LKB1 co-mutated NSCLC.

Abstract 5805: Palbociclib synergistically enhances the anticancer activity of cisplatin in P53 mutant model of upper gastrointestinal cancers

Abstract Background: Upper Gastrointestinal Cancers (UGCs) respond poorly to conventional chemotherapy due to overactive intrinsic mechanisms that mediate cellular proliferation and drug resistance. Dysregulated cell division due to increased activity of cyclin-dependent kinases 4/6 (CDK4/6) is one such mechanism that drives progression of UGCs, making them an important therapeutic target. Palbociclib is a second generation cdk4/6 specific inhibitor approved for treatment of ER+ breast cancers. Since Cisplatin (CDDP) is a first line therapeutic agent frequently used for treatment of UGCs we hypothesized that Palbociclib would complement the DNA-damaging activity of CDDP. To test this hypothesis, we investigated the potential therapeutic benefit of Palbociclib alone and in combination with CDDP in P53 mutant model of UGCs. Methods: In this study, we evaluated the effect of Palbociclib treatment alone and/or in combination with CDDP on FLO-1 (P53 mutant) UGC cell viability, survival, and cell cycle progression, respectviely. The MTT cell viability assay and Compusyn mediated median effect plot analysis (MEPA)(Chou and Talaly) were used to determine synergistic drug combinations of Palbociclib and CDDP in FLO-1 UGC cells. Results: The cell viability data and MEPA indicated that Palbociclib and CDDP show significant synergistic anticancer activity in FLO-1 UGC cells at a ratio of 1:2 and 1:3, respectively. The clonogenic cell survival assay data showed that in comparison to treatment with Palbociclib (0.5µM) or CDDP (1.0 and 1.5µM) alone, the combination treatments (Palbociclib:CDDP) at a ratio of 1:2 and 1:3 exhibited significantly elevated (p&amp;lt;0.05) inhibition of cellular survival in FLO-1 UGC cell lines. In addition, the Combination Index (CI) values of 0.66 and 0.71 for the aforementioned combination ratios suggests a strong synergism between the two drugs. Furthermore, the cell cycle data exhibited a marked increase (p&amp;lt;0.05) in the percentage of FLO-1 cells in the sub-G1-phase (cell death) after treatment with Palbocicb and CDDP combinations for 72 hrs., respectively . Conclusions: Our in vitro data indicate that Palbociclib, as a single agent, is an effective therapeutic strategy for inhibiting UGC cells. Additionally, Palbociclib in combination with CDDP synergistically enhances the anti-tumor activity of CDDP against P53 mutant UGC cells[MM1] . The observed synergism can potentially translate into reduced individual drug dosages and toxicity for Palbociclib and/or CDDP when used in combination. Citation Format: Dhvanir Kansara, Amruta Samant, Priya Pancholi, Tanvi Visal, Shraddha Patel, Vikas Sehdev. Palbociclib synergistically enhances the anticancer activity of cisplatin in P53 mutant model of upper gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5805.

C60 fullerene enhances cisplatin anticancer activity and overcomes tumor cell drug resistance

We formulated and analyzed a novel nanoformulation of the anticancer drug cisplatin (Cis) with C60 fullerene (C60+Cis complex) and showed its higher toxicity toward tumor cell lines in vitro when compared to Cis alone. The highest toxicity of the complex was observed in HL-60/adr and HL-60/vinc chemotherapy-resistant human leukemia cell sublines (resistant to Adriamycin and Vinculin, respectively). We discovered that the action of the C60+Cis complex is associated with overcoming the drug resistance of the tumor cell lines through observing an increased number of apoptotic cells in the Annexin V/PI assay. Moreover, in vivo assays with Lewis lung carcinoma (LLC) C57BL/6J male mice showed that the C60+Cis complex increases tumor growth inhibition, when compared to Cis or C60 fullerenes alone. Simultaneously, we conducted a molecular docking study and performed an Ames test. Molecular docking specifies the capability of a C60 fullerene to form van der Waals interactions with potential binding sites on P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP-1), and multidrug resistance protein 2 (MRP-2) molecules. The observed phenomenon revealed a possible mechanism to bypass tumor cell drug resistance by the C60+Cis complex. Additionally, the results of the Ames test show that the formation of such a complex diminishes the Cis mutagenic activity and may reduce the probability of secondary neoplasm formation. In conclusion, the C60+Cis complex effectively induced tumor cell death in vitro and inhibited tumor growth in vivo, overcoming drug resistance likely by the potential of the C60 fullerene to interact with P-gp, MRP-1, and MRP-2 molecules. Thus, the C60+Cis complex might be a potential novel chemotherapy modification.

Reversal of platinum drug resistance by the histone deacetylase inhibitor belinostat

ObjectivesTo investigate and elucidate the mechanism for the potentiation of cisplatin anticancer activity by belinostat in platinum (Pt)-resistant lung cancer cells. Materials and methodsCombination of cisplatin and belinostat was investigated in two pairs of parental and cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines. The Pt-resistant cell models exhibited overexpression of the efflux transporter ABCC2 and enhanced DNA repair capacity. Cellular accumulation of cisplatin and extent of DNA platination were measured by inductively coupled plasma optical emission spectrometer. Expression of Pt transporters and DNA repair gene were determined by quantitative real-time PCR. Inhibition of ABCC2 transport activity was examined by flow cytometric assay. Regulation of ABCC2 at the promoter level was studied by chromatin immunoprecipitation assay. Results and conclusionIn Pt-resistant lung cancer cells, belinostat apparently circumvent the resistance through inhibition of both ABCC2 and DNA repair-mediated mechanisms. The combination of belinostat and cisplatin were found to display synergistic cytotoxic effect in cisplatin-resistant lung cancer cell lines when the two drugs were added concomitantly or when belinostat was given before cisplatin. Upon the concomitant administration of belinostat, cellular accumulation of cisplatin and formation of DNA-Pt adducts were found to be increased whereas expression levels of the efflux transporter ABCC2 and the DNA repair gene ERCC1 were inhibited in Pt-resistant cells. Belinostat-mediated downregulation of ABCC2 was associated with an increase association of a transcriptional repressor (negative cofactor 2) but reduced association of a transcriptional activator (TFIIB) to the ABCC2 promoter. The data advocates the use of belinostat as a novel drug resistance reversal agent for use in combination cancer chemotherapeutic regimens.

Abstract 3733: Augmentation of response to therapeutic agents by (-)-gallocatechin gallate through inhibition of RAD51 nuclear translocation

Abstract Lung cancer is the most common cancer worldwide. Platinum-based combination chemotherapy is one of first line treatments for patients with lung cancer. Most of the cytotoxic drugs are targeting DNA, interfere with DNA synthesis, and triggering DNA damage response (DDR). Since DDR usually activates important defensive pathways to repair damaged DNA, DDR is known as a key factor determining the outcome of chemotherapy. Among them, RAD51, playing a central role in homologous recombination (HR) DNA repair, has been shown to interfere with the prognosis of patients treated with chemoradiotherapy. Since we have demonstrated that inhibition of RAD51 nuclear focus formation synergistically enhances the anticancer activity of cisplatin, we further screened purified natural products in order to find products with activity to inhibit RAD51 nuclear focus formation. In the present study, we found that a green tea catechin derivative, the (-)-Gallocatechin gallate (GCG) has potent inhibitory activity against RAD51 nuclear focus formation in cisplatin-treated H460 cells. The in vitro cytotoxicity assay showed that the combination of cisplatin or irinotecan with GCG significantly increases the sensitivity of H460 cells to these DNA damage agents. We also evaluated the anti-tumor growth activity of cisplatin or irinotecan in combination with GCG using H460 xenografts. Our results showed that cisplatin and irinotecan suppresses tumor growth by 17.6% and 33.8%, while in combination with GCG suppresses tumor growth by 52.2% and 68.9%, respectively. We further demonstrated that GCG is able to inhibit cisplatin-induced ATM and Chk2 phosphorylation. Together, our results suggest that GCG may interfere with ATM-Chk2 pathway and hence suppress RAD51 nuclear focus formation and DNA repair activities. Citation Format: Ming-Hsi Wu, Lie-Chwen Lin, Te-Chang Lee. Augmentation of response to therapeutic agents by (-)-gallocatechin gallate through inhibition of RAD51 nuclear translocation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3733.