Cancer cell resistance to chemotherapy drugs such as Gemcitabine, Oxaliplatin, Cisplatin, Doxorubicin, and 5-fluorouracil account for the main reason of chemotherapy failure for HCC patients, especially for those with advanced HCC or metastasis patients. This emerging resistance limits the effectiveness and clinical application of these chemotherapy drugs. Previous studies reported that drug-resistant tumor cell-derived exosomes could transfer their resistance property to tumor sensitive cells in some cancer, including lung and gastric cancer. This study sought to explore whether HepG2/DDP cell-derived exosomes transmit cisplatin (DDP) resistance to HepG2 and other HCC sensitive cells, and provide considerable guidance for HCC nursing with Cisplatin DDP clinically.

Enzymatic gold nanoparticles (B-GNPs) have been synthesized using a natural anticancer agent bromelain (a cysteine protease) and these nanoparticles were used to bioconjugate Cisplatin (highly effective against osteosarcoma and lung cancer). Cisplatin bioconjugated bromelain encapsulated gold nanoparticles (B-C-GNPs) were found profoundly potent against same cancers at much lower concentration with minimum side effects due to the synergistic effect of bromelain. The B-C-GNPs have been observed to inhibit the proliferation of osteosarcoma cell lines Saos-2 and MG-63 with IC50 estimation of 4.51 µg/ml and 3.21 µg/ml, respectively, and against small lung cancer cell line A-549 with IC50 2.5 µg/ml which is lower than IC50 of cisplatin against same cell lines. The B-GNPs/B-C-GNPs were characterized by TEM, UV-Visible spectroscopy, Zeta potential and DLS to confirm the production, purity, crystalline nature, stability of nanoemulsion, size and shape distribution. The change in 2D and 3D conformation of bromelain after encapsulation was studied by Circular Dichroism and Fluorometry, respectively. It was found that after encapsulation, a 19.4% loss in secondary structure was observed, but tertiary structure was not altered significantly and this loss improved the anticancer activity. The confirmation of bioconjugation of cisplatin with B-GNPs was done by UV-Visible spectroscopy, TEM, FTIR, 2D 1H NMR DOSY and ICP-MS. Further, it was found that almost ~4 cisplatin molecules bound with each B-GNPs nanoparticle.

Pretreatment with magnesium (Mg) has been reported to attenuate cisplatin (CDDP)-induced nephrotoxicity (CIN). This attenuation involves modulation of the expression of renal transporters, resulting in reduced renal platinum accumulation after a single round of CDDP treatment. In this study, we investigated whether Mg co-administration ameliorates CIN after multiple doses of CDDP as effectively as after a single dose.

Thioridazine was used to sensitize cisplatin against cisplatin-resistant human lung cancer cells. Cells received thioridazine, cisplatin, or both drugs (the combination). Thioridazine synergized cisplatin to increase percentages of dead and apoptotic cells. DNA damage was detected using the comet assays; the combination led to the highest alkaline- and neutral-comet percentages, demonstrating exacerbation of both single- and double-strand breaks. After thioridazine treatment, levels of glutathione, and BRCA2, RAD51, and ERCC1 proteins were decreased. These data manifested that thioridazine decreased the capacities of detoxification and DNA repair, thereby enhancing cisplatin-induced DNA damage in resistant cells.

Cisplatin has a well-established role in the treatment of broad spectrum of malignancies; however its use is limited because of cisplatin-induced nephrotoxicity (CIN) which can be progressive in more than 50% of cases. The most important risk factors for CIN include higher doses of cisplatin, previous cisplatin chemotherapy, underlying kidney damage and concurrent treatment with other potential nephrotoxin agents, such as aminoglycosides, nonsteroidal anti-inflammatory agents, or iodinated contrast media. Different strategies have been offered to diminish or prevent nephrotoxicity of cisplatin. The standard approach for prevention of CIN is the administration of lower doses of cisplatin in combination with full intravenous hydration prior and after cisplatin administration. Cisplatin-induced oxidative stress in the kidney may be prevented by natural antioxidant compounds. The results of this review show that many strategies for prevention of CIN exist, however, attention to the administration of these agent for CIN is necessary.

Cisplatin is one of the most common drugs used for treatment of solid tumors such as ovarian cancer. Unfortunately, the development of resistance against this cytotoxic agent limits its clinical use. Here we report that YSY01A, a novel proteasome inhibitor, is capable of suppressing survival of cisplatin-resistant ovarian cancer cells by inducing apoptosis. And YSY01A treatment enhances the cytotoxicity of cisplatin in drug-resistant ovarian cancer cells. Specifically, YSY01A abrogates regulatory proteins important for cell proliferation and anti-apoptosis including NF-κB p65 and STAT3, resulting in down-regulation of Bcl-2. A dramatic increase in cisplatin uptake was also observed by inductively coupled plasma-mass spectrometry following exposure to YSY01A. Taken together, YSY01A serves as a potential candidate for further development as anticancer therapeutics targeting the proteasome.

Cisplatin (cDDP) is known to bind to the CXXC motif of proteins containing a ferrodoxin-like fold but little is known about its ability to interact with other Cu-binding proteins. MEK1/2 has recently been identified as a Cu-dependent enzyme that does not contain a CXXC motif. We found that cDDP bound to and inhibited the activity of recombinant MEK1 with an IC50 of 0.28 μM and MEK1/2 in whole cells with an IC50 of 37.4 μM. The inhibition of MEK1/2 was relieved by both Cu+1 and Cu+2 in a concentration-dependent manner. cDDP did not inhibit the upstream pathways responsible for activating MEK1/2, and did not cause an acute depletion of cellular Cu that could account for the reduction in MEK1/2 activity. cDDP was found to bind MEK1/2 in whole cells and the extent of binding was augmented by supplementary Cu and reduced by Cu chelation. Molecular modeling predicts 3 Cu and cDDP binding sites and quantum chemistry calculations indicate that cDDP would be expected to displace Cu from each of these sites. We conclude that, at clinically relevant concentrations, cDDP binds to and inhibits MEK1/2 and that both the binding and inhibitory activity are related to its interaction with Cu bound to MEK1/2. This may provide the basis for useful interactions of cDDP with other drugs that inhibit MAPK pathway signaling.

Chemotherapy drugs, such as cisplatin (DDP), improve the survival of patients with lung cancer by inducing apoptosis in cancer cells, which quickly develop resistance to DDP through uncharacterized mechanisms. Glioma Pathogenesis-Related Protein 1 (GLIPR1) plays an important role in cell proliferation, migration and apoptosis. However, the expression and function of GLIPR1 in mediating DDP resistance in human lung adenocarcinoma A549/DDP and human large cell lung cancer H460/DDP cells has not yet been reported.

Cisplatin-resistant ovarian cancer occurs in patients with ovarian cancer treated with cisplatin-based chemotherapy, which results in tumor progression during treatment, or recurrence of the tumor within 6 months of the treatment. It is vital that a novel biomarker for diagnosis, or an efficient therapeutic target of cisplatin-resistant ovarian is identified. Long non-coding (lnc)RNAs were determined to serve critical functions in a variety of distinct types of cancer, including ovarian cancer; however, there is limited knowledge regarding the differential expression levels of lncRNAs in cisplatin-resistant and cisplatin-sensitive ovarian cancer. Therefore, in the present study, the expression levels were determined for these cancer types. The lncRNA expression profile in cisplatin-resistant ovarian cancer was analyzed and compared with the results for cisplatin-sensitive ovarian cancer; gene ontology and pathway analysis demonstrated that the dysregulated lncRNAs participated in important biological processes. Subsequently, it was identified that these dysregulated lncRNAs were present in other ovarian cancer tissues and in SKOV3 ovarian cancer cells, as well as its cisplatin-resistant clone, SKOV3/CDDP. In addition, it was revealed that 8 lncRNAs (Enst0000435726, Enst00000585612, Enst00000566734, Enst00000453783, NR_023915, RP11_697E22.2, uc010jub.1 and tcons_00008505) were associated with cisplatin-resistant ovarian cancer. The present study may assist in improving understanding of the initiation and developmental mechanisms underlying cisplatin-resistant ovarian cancer, which could aid future studies in discovering potential biomarkers for diagnosis or therapeutic targets that may be used in clinical treatment.

The protein phosphatase 2A (PP2A) inhibitor, LB100, has been shown in pre-clinical studies to be an effective chemo- and radio-sensitizer for treatment of various cancers. We investigated effects associated with LB100 treatment alone and in combination with cisplatin for medulloblastoma (MB) in vitro and in vivo in an intracranial xenograft model. We demonstrated that LB100 had a potent effect on MB cells. By itself, LB100 inhibited proliferation and induced significant apoptosis in a range of pediatric MB cell lines. It also attenuated MB cell migration, a pre-requirement for invasion. When used in combination, LB100 enhanced cisplatin-mediated cytotoxic effects. Cell viability in the presence of 1 uM cisplatin alone was 61% (DAOY), 100% (D341), and 58% (D283), but decreased with the addition of 2 μM of LB100 to 26% (DAOY), 67% (D341), and 27% (D283), (p < 0.005). LB100 suppressed phosphorylation of the STAT3 protein and several STAT3 downstream targets. Also, LB100 directly increased cisplatin uptake and overcame cisplatin-resistance in vitro. Finally, LB100 exhibited potent in vivo anti-neoplastic activity in combination with cisplatin in an intracranial xenograft model.

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment.

MicroRNAs play a critical role in chemoresistance and are implicated in various biological and pathological processes of cells. The objective of the present study was to explore the role of miR‑133b and its mechanism in the regulation of cisplatin resistance and tumor progression in cisplatin‑resistant non‑small cell lung cancer (NSCLC) cells. Reverse transcription‑quantitative polymerase chain reaction and western blot assays of the cisplatin‑resistant cell lines A549/DPP and H1299/DDP displayed the reduced expression of miR‑133b and increased expression of glutathione-S-transferase P1 (GSTP1) in the resistant cells compared with the respective parental cell lines A549 and H1299. Cell Counting kit‑8, flow cytometry, colony formation and Transwell migration assays indicated that the overexpression of miR‑133b increased the chemosensitivity to cisplatin and attenuated the proliferation and migration capacities of the cisplatin‑resistant NSCLC cell lines in vitro. A dual‑luciferase reporter assay demonstrated that miR‑133b negatively regulated the expression of GSTP1 by targeting its 3'‑untranslated region. In addition, the knockdown of GSTP1 by transfection with small interfering RNA exerted similar effects on cell chemosensitivity, proliferation and migration as did ectopic miR‑133b expression, in addition to the upregulation of Bax and downregulation of Bcl‑2, survivin and matrix metalloproteinase expression. In conclusion, the present study findings provide the insights that miR‑133b reduces cisplatin resistance and its overexpression contributes to the suppression of the malignant growth and aggressiveness of cisplatin‑resistant NSCLC cells by targeting GSTP1. This could potentially be exploited as a novel therapeutic strategy for the reversal of cisplatin resistance.

We previously reported that the concomitant use of enalapril and telmisartan exacerbates the risk of cisplatin (CDDP)-induced acute renal dysfunction compared to other antihypertensive drugs in mice. Thus, in the current study, we investigated the risk of developing chronic kidney disease following repeated concomitant use of CDDP and antihypertensive drugs.

Acquired resistance of chemotherapy, especially cisplatin, is a major challenge in lung cancer treatment. We conducted this study to examine whether a cyclin D kinase 4/6 (CDK4/6) inhibitor, PD 0332991, could reverse cisplatin resistance in human lung cancer cells. In addition, we explored the underlying mechanisms.

The antagonistic effect of glutathione (GSH) against the cytotoxicity of cisplatin was observed in both wild type and cisplatin-resistant human leukaemia and ovarian carcinoma cell lines. The simultaneous presence of the cytotoxic copper complex [Cu(phen)2(OH2)](ClO4)2 (C0) restored the sensitivity of the cells to cisplatin, and, at selected concentrations, led to strong synergistic effects. The C0-cisplatin-glutathione system showed a synergistic toxic effect even in the presence of 1000 μM GSH. The three-drug cocktail exerted a higher potency against leukemic cells than against freshly isolated lymphocytes from healthy donors. Compared to actively proliferating normal lymphocytes, leukaemia cells were much more susceptible to the cytocide effect of the three-drug combination and underwent the dying process(es) much faster. When the ovarian carcinoma cells were treated with cisplatin, alone or in combination with C0, late apoptotic effects were mainly observed, suggesting that DNA interactions with the C0-cisplatin complex trigger a process of programmed cell death. In contrast, the ternary combination induced apoptotic effects similar to that shown by C0 in single treatment, that is, early apoptosis. One possible explanation is that C0 and cisplatin compete for GSH-binding in the culture medium. GSH in combination with C0 and cisplatin caused a significant induction of the apoptotic process(es), through a pathway which does not compromise the integrity of the plasma membrane of cells.

Standard chemotherapy for ovarian cancers is often abrogated by drug resistance. Specifically, resistance to cisplatin is a major clinical obstacle to successful treatment of ovarian cancers. The aim of this study was to develop a therapeutic strategy using natural killer (NK) cells to treat cisplatin-resistant ovarian cancers. First, we compared the responses of ovarian cancer cell line A2780 and its cisplatin-resistant counterpart, A2780cis, to treatment with cisplatin plus NK92MI cells. Although combined treatment induces apoptosis of ovarian cancer cells via ROS-dependent and -independent mechanisms, A2780cis were resistant to NK92MI cell-mediated cytotoxicity. We found that A2780cis cells showed markedly higher expression of immune checkpoint protein, PD-L1, than the parental cells. Although pretreatment of A2780cis cells with cisplatin stimulated further expression of PD-L1, it also increased expression of ULBP ligands, which are activating receptors on NK92MI cells, both in vitro and in vivo. These findings suggest that combined use of cisplatin plus NK cell-mediated immunotherapy could overcome immunoresistance of chemoresistant ovarian cancers.

Due to their short-range (2-500 nm), Auger electrons (Auger e-) have the potential to induce nano-scale physiochemical damage to biomolecules. Although DNA is the primary target of Auger e-, it remains challenging to maximize the interaction between Auger e- and DNA. To assess the DNA-damaging effect of Auger e- released as close as possible to DNA without chemical damage, we radio-synthesized no-carrier-added (n.c.a.) [189, 191Pt]cisplatin and evaluated both its in vitro properties and DNA-damaging effect. Cellular uptake, intracellular distribution, and DNA binding were investigated, and DNA double-strand breaks (DSBs) were evaluated by immunofluorescence staining of γH2AX and gel electrophoresis of plasmid DNA. Approximately 20% of intracellular radio-Pt was in a nucleus, and about 2% of intra-nucleus radio-Pt bound to DNA, although uptake of n.c.a. radio-cisplatin was low (0.6% incubated dose after 25-h incubation), resulting in the frequency of cells with γH2AX foci was low (1%). Nevertheless, some cells treated with radio-cisplatin had γH2AX aggregates unlike non-radioactive cisplatin. These findings suggest n.c.a. radio-cisplatin binding to DNA causes severe DSBs by the release of Auger e- very close to DNA without chemical damage by carriers. Efficient radio-drug delivery to DNA is necessary for successful clinical application of Auger e-.

Astaxanthine (AST) has important biological activities including antioxidant and anti-inflammatory effects that could alleviate neurological and heart diseases, but its role in the prevention of cisplatin-induced hearing loss (CIHL) is not yet well understood. In our study, a steady interaction between AST and the E3 ligase adapter Kelch-like ECH-associated protein 1, a predominant repressor of nuclear factor erythroid 2-related factor 2 (NRF2), was performed and tested via computer molecular docking and dynamics. AST protected against cisplatin-induced ototoxicity via NRF2 mediated pathway using quantitative PCR and Western blotting. The levels of reactive oxygen species (ROS) and mitochondrial membrane potential revealed that AST reduced ROS overexpression and mitochondrial dysfunction. Moreover, AST exerted anti-apoptosis effects in mouse cochlear explants using immunofluorescence staining and HEI-OC1 cell lines using quantitative PCR and Western blotting. Finally, AST combined with poloxamer was injected into the middle ear through the tympanum, and the protection against CIHL was evaluated using the acoustic brain stem test and immunofluorescent staining in adult mice. Our results suggest that AST reduced ROS overexpression, mitochondrial dysfunction, and apoptosis via NRF2-mediated pathway in cisplatin-exposed HEI-OC1 cell lines and mouse cochlear explants, finally promoting cell survival. Our study demonstrates that AST is a candidate therapeutic agent for CIHL.

Although Cisplatin (DDP) is a widely used first-line chemotherapy medication, DDP resistance is one of the main causes of treatment failure in advanced lung cancer. Therefore, it is urgent to identify DDP sensitizers and investigate the underlying molecular mechanisms. Here we utilized DDP-resistant organoids established from tumor biopsies of patients with relapsed lung cancers. In this study, we identified Solamargine as a potential DDP sensitizer through screening a natural product library. Mechanically, Solamargine induced G0/G1-phase arrest and apoptosis in DDP-resistant lung cancer cell lines. Gene expression analysis and KEGG pathway analysis indicated that the hedgehog pathway was suppressed by Solamargine. Moreover, Gli responsive element (GRE) reporter gene assay and BODIPY-cyclopamine binding assay showed that Solamargine inhibited the hedgehog pathway via direct binding to SMO protein. Interestingly, Solamargine and DDP showed a synergetic effect in inhibiting DDP-resistant lung cancer cell lines. Taken together, our work herein revealed Solamargine as a hedgehog pathway inhibitor and DDP-sensitizer, which might provide a new direction for further treatment of advanced DDP-resistant lung cancer patients.

Cisplatin is a chemotherapy drug that kills cancer cells by damaging their DNA. In human cells, this damage is repaired primarily by nucleotide excision repair. While cisplatin is generally effective, many cancers exhibit initial or acquired resistance to it. Here, we studied cisplatin resistance in a defined cell line system. We conducted a comprehensive genomic characterization of the cisplatin-sensitive A2780 ovarian cancer cell line compared to A2780cis, its resistant derivative. The resistant cells acquired less damage, but had similar repair kinetics. Genome-wide mapping of nucleotide excision repair showed a shift in the resistant cells from global genome towards transcription-coupled repair. By mapping gene expression changes following cisplatin treatment, we identified 56 upregulated genes that have higher basal expression in the resistant cell line, suggesting they are primed for a cisplatin response. More than half of these genes are novel to cisplatin- or damage-response. Six out of seven primed genes tested were upregulated in response to cisplatin in additional cell lines, making them attractive candidates for future investigation. These novel candidates for cisplatin resistance could prove to be important prognostic markers or targets for tailored combined therapy in the future.