Cis-diaminedichloroplatinum Research Articles

A Chinese Medicine Compound Alleviates Cisplatin-Induced Acute Kidney Injury via Its Antiapoptosis and Anti-Inflammation Effects in Mice.

Cisplatin, also known as cis-diamine dichloroplatinum (CDDP), is a widely used chemotherapeutic drug. However, its application is limited by the occurrence of serious nephrotoxicity. Currently, no effective therapy is available for combating CDDP-induced acute kidney injury (AKI). In the present study, we investigated the efficacy of Jianpi Yishen Tang (JPYST), a traditional Chinese medicine (TCM) compound commonly used to treat chronic kidney disease, against CDDP-induced AKI. In the CDDP + JPYST group, male mice were pretreated with JPYST (18.35 g/kg/day) for 5 consecutive days before receiving a single dose of CDDP (20 mg/kg), all mice were sacrificed 72 h after the CDDP injection. Results showed that JPYST suppressed CDDP-induced kidney dysfunction and tubular damage scores in the mice. Mechanistically, JPYST treatment attenuated CDDP-induced renal tubular cell apoptosis in AKI mice, as manifested by a marked decreased in TUNEL-positive cell counts, downregulation of the pro-apoptotic proteins Bax, Bad and caspase 3, and upregulation of the antiapoptotic protein Bcl-2 in kidney tissues. Meanwhile, JPYST decreased the expression of inflammatory cytokines TNF-α, IL-1β, and IL-6 in the serum and renal tissues of mice following CDDP administration. These factors are involved in suppressing the activation of phospho-NF-κB p65 in tubular epithelial cells. Taken together, these findings demonstrated that JPYST exerts renoprotective effects against CDDP-induced AKI through antiapoptosis and anti-inflammation effects, and these are associated with downregulation of NF-κB activation. Therefore, JPYST has potential for development of treatment therapies against CDDP-induced AKI.

Advancements in the Use of Platinum Complexes as Anticancer Agents.

The platinum (II) complexes as anticancer agents have been well explored for the development of novel analogs. Yet, none of them achieved clinical importance in oncology. At present, anticancer compounds containing platinum (II) complexes have been employed in the treatment of colorectal, lung, and genitourinary tumors. Among the platinum-based anticancer drugs, Cisplatin (cis-diamine dichloroplatinum (II), cis-[Pt(NH3)2Cl2]) is one of the most potent components of cancer chemotherapy. The nephrotoxicity, neurotoxicity and ototoxicity, and platinum compounds associated resistant cancer are some major disadvantages. With the rapidly growing interest in platinum (II) complexes in tumor chemotherapy, researchers have synthesized many new platinum analogs as anticancer agents that show better cytotoxicity, and less off-target effects with less cellular resistance. This follows the introduction of oxaliplatin, water-soluble carboplatin, multinuclear platinum and newly synthesized complexes, etc. Methods: This review emphasizes recent advancements in drug design and development, the mechanism of platinum (II) complexes, their stereochemistry, current updates, and biomedical applications of platinum-based anticancer agents. In the last few decades, the popularity of platinum complexes as potent anti-cancer agents has risen as scientists have synthesized many new platinum complexes that exhibit better cytotoxicity coupled with less off-target effects.

Preparation of Magnetic Drug Loaded Nanoparticles and Its Anticancer Efficacy Against Nasopharyngeal Carcinoma Cells

As an important drug for the treatment of cancer, cis-diamine dichloroplatinum (CDDP) has poor solubility and antagonistic effect when it is used as a chemotherapy agent alone, leading to the insufficient dose in actual administration. In order to solve the above problems, increase the targeting property of CDDP carrier and prolong the half-life period of CDDP’s sustained-release, it is necessary to design a magnetic nano-carrier for CDDP with magnetic targeting function to reduce the damage of CDDP to normal tissues in vivo and improve the therapeutic effect of cancer. Carboxymethyl chitosan (CMCS) is used to directly coat oleic acid (OA)-modified Fe3O4 nanoparticles (OA-Fe3O4 NPs) to create the nano-scale CMCS magnetic nanoparticles (CMCS/OA-Fe2O3 NPs), and CDDP loaded magnetic nanoparticles (CMCS/OA-Fe2O3 NPs/CDDP) are prepared by the bonding interaction between carboxyl groups on the surface of CMCS and the anticancer drug CDDP. The magnetic drug loaded nanoparticles are characterized, and the results show that the magnetic nanoparticles are successfully embedded in CMCS and loaded with CDDP, with the drug load of 43.65 ± 2.37%. MTT assay, flow cytometry and invasion assay are applied to evaluate the inhibitory effect of magnetic drug loaded nanoparticles to nasopharyngeal carcinoma (NPC) cells HNE-1. The results suggest that the magnetic drug loaded nanoparticles successfully prepared have significant inhibitory effect on HNE-1 cells in vitro. Therefore, the magnetic drug loaded nanoparticles prepared have a good therapeutic effect on NPC.

Plasma Gelsolin Inhibits CD8+ T-cell Function and Regulates Glutathione Production to Confer Chemoresistance in Ovarian Cancer.

Although initial treatment of ovarian cancer is successful, tumors typically relapse and become resistant to treatment. Because of poor infiltration of effector T cells, patients are mostly unresponsive to immunotherapy. Plasma gelsolin (pGSN) is transported by exosomes (small extracellular vesicle, sEV) and plays a key role in ovarian cancer chemoresistance, yet little is known about its role in immunosurveillance. Here, we report the immunomodulatory roles of sEV-pGSN in ovarian cancer chemoresistance. In chemosensitive conditions, secretion of sEV-pGSN was low, allowing for optimal CD8+ T-cell function. This resulted in increased T-cell secretion of IFNγ, which reduced intracellular glutathione (GSH) production and sensitized chemosensitive cells to cis-diaminedichloroplatinum (CDDP)-induced apoptosis. In chemoresistant conditions, increased secretion of sEV-pGSN by ovarian cancer cells induced apoptosis in CD8+ T cells. IFNγ secretion was therefore reduced, resulting in high GSH production and resistance to CDDP-induced death in ovarian cancer cells. These findings support our hypothesis that sEV-pGSN attenuates immunosurveillance and regulates GSH biosynthesis, a phenomenon that contributes to chemoresistance in ovarian cancer. SIGNIFICANCE: These findings provide new insight into pGSN-mediated immune cell dysfunction in ovarian cancer chemoresistance and demonstrate how this dysfunction can be exploited to enhance immunotherapy.

Telmisartan Exacerbates Cisplatin-Induced Nephrotoxicity in a Mouse Model.

Cisplatin (CDDP; cis-diamine dichloroplatinum)-induced nephrotoxicity is the main reason for dose limitations, which can reduce the efficacy of cancer treatment. Lower blood pressure and administration of renin angiotensin system (RAS) inhibitors have been reported as factors that exacerbate CDDP-induced nephrotoxicity; however, the detailed mechanisms remain unknown and the results of previous studies are conflicting. In this study, we examined the influence of various hypotensive drugs, including RAS inhibitors and calcium channel blockers, on CDDP-induced nephrotoxicity in BALB/c mice. The mice were divided into nine groups: (1) CDDP group (15 mg/kg CDDP), (2) AML group (5 mg/kg amlodipine), (3) ENA group (2.5 mg/kg enalapril), (4) telmisartan (TEL) group (10 mg/kg telmisartan), (5) LOS group (10 mg/kg losartan), (6) CDDP + AML group, (7) CDDP + ENA group, (8) CDDP + TEL group, and (9) CDDP + LOS group. Nephrotoxicity was evaluated by measuring serum creatinine (CRE) and blood urea nitrogen (BUN) levels. In addition, the kidney sections were stained with Masson's trichrome and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) to assess the renal fibrosis area and apoptotic area. Serum CRE and BUN levels were increased in the CDDP + ENA, CDDP + LOS, and CDDP + TEL groups compared to those in the CDDP alone group, and the CDDP + AML group showed an increasing trend. However, there was no correlation between ∆CRE or ∆BUN levels and ∆ systolic blood pressure. The CDDP + TEL group showed a significant increase in the renal fibrosis area. These results suggest that exacerbation of CDDP-induced nephrotoxicity is not correlated with systolic blood pressure but is associated with administration of RAS inhibitors, particularly TEL.

Effect of miR-26b-5p on cis-diamine dichloroplatinum-induced ovarian granulosa cell injury by targeting MAP3K9.

The proliferation and differentiation of granulosa cells are very important for follicular development. The dysfunction of granulosa cells leading to follicular development is an important cause of ovarian endocrine abnormalities. More and more evidence shows that microRNAs are involved in the regulation of ovarian granulosa cell function. It has been found that MiR-26b may be involved in CDDP resistance. Studies have shown that miR-26b can promote apoptosis of ovarian granulosa cells, but there are few studies on its mechanism, and no studies have been found on the damage of miR-26b-5p to rat ovarian granulosa cells induced by CDDP. Identification of ovarian granulosa cells was conductedby immunochemical staining. Cell counting kit 8 (CCK-8) was used to detect cell viability, flow cytometry was used to detect cell apoptosis, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot (WB) were used to analyze the expression of miR-26b-5p, MAP3K9, cleaved Caspase-3, Bax, and Bcl-2; dual-luciferase reporter assay results further verify the targeting relation between miR-26b-5p and MAP3K9. CDDP remarkably inhibited ovarian granulosa cell viability and induced ovarian granulosa cell apoptosis; miR-26b-5p inhibitor enhanced viability and inhibited apoptosis of ovarian granulosa cells, which treated with CDDP, but had little effect on normal cells. MAP3K9 partially reversed the effect of miR-26b-5p on ovarian granulosa cells induced by CDDP. miR-26b-5p has a protective effect on CDDP-induced ovarian granulosa cells via targeting MAP3K9.

Water extract of ginseng and astragalus regulates macrophage polarization and synergistically enhances DDP's anticancer effect

Ethnopharmacological relevanceIn traditional Chinese medicine, supplementing Qi and strengthening body resistance are an important principle of anticancer treatment. Panax ginseng C.A.Mey. (ginseng) and Astragalus membranaceus Bunge (astragalus) are the representative herbs for this therapeutic principle. Aim of the studyThis study aims to explore the effect of the water extract of ginseng and astragalus (WEGA) on regulating macrophage polarization and mediating anticancer in the tumor microenvironment. Materials and methodsA549 cells were cultured in tumor-associated macrophage (TAM) supernatant with various concentrations of WEGA (0, 5, 10, 20 mg/mL). A549 cell proliferation was determined through methyl thiazole tetrazolium (MTT) assay and real-time cell analysis (RTCA), respectively. In vivo experiments were performed with a Lewis lung cancer (LLC) xenograft mouse model. Forty-eight mice were divided into six groups and treated with saline, WEGA, or cis-diamine dichloro platinum (DDP) with dosage of WEGA (0, 30, 60, 120 mg/kg body weight/day). The different groups were administered with drugs via oral or intraperitoneal injection once a day for 21 consecutive days. Tumor inhibition rate, spleen index, thymus index, cytokine, protein, and mRNA expression levels were detected in mice. ResultsIn a co-culture system, WEGA remarkably inhibited A549 cell proliferation, promoted the expression of M1 macrophage markers and inhibited M2 TAMs markers. Therefore, WEGA affected the biological behavior of cancer cells by regulating the expression of some markers relevant to macrophage polarization. In addition, the group of WEGA and DDP chemotherapy effectively inhibited the transplanted tumor growth in mice and improved weight loss and immunosuppressive with the cisplatin inducing. ConclusionsThis study provides mechanistic insights into the anticancer effect of WEGA through the regulation of macrophage polarization and highlights that WEGA could be a novel option for integrative cancer therapies.

Preparation and Characterization of Solid Lipid Nanoparticles Loaded with Cisplatin

Cisplatin (Cis diaminedichloro platinum) was the first platinum drug to be used as an anticancer drug, and it is widely used in the treatment of testicular, head, neck, ovarian and lung cancer. The use of Cisplatin is limited due to its intrinsic and acquired resistance and severe side effects such as chronic neurotoxicity and nephrotoxicity. The colloidal carriers such as emulsion, liposomes, polymeric nanoparticles have been extensively studied to overcome above limitations. The solid lipid nanoparticles (SLNs), amongst other colloidal carriers, were found to be an ideal carrier for lipophillic drug for better stability and release retardation. Cisplatin loaded solid lipid nanoparticles was prepared by microemulsion technique. Stearic acid was used as lipid. The other excipients were used as DPPG, Soya lecithin and Poloxamer P407 and acidic buffer PH4. Also used Probe sonication for 10 min at 79 Amplitude. Cisplatin SLNs Batch C13 showed particle size of 119.23±1.52 nm, Zeta potential of -37.33±2.47 mV, % Entrapment efficiency of 90.2 ± 2.1 %., % Drug loading capacity of 1.62 ± 1.34 %., The TEM study of optimized Cisplatin SLN illustrated the spherical shape of nanoparticles. Total release amount of Cisplatin was 82.62± 2.04 % after 48 hrs. The formulation performed kinetics study followed Peppas plot equation The SLNs of Cisplatin met all the requirements of a colloidal drug delivery system. They had particle size in nanosize; their size distribution was narrow and all the particles were in spherical shape and stable.
 Keywords: Cisplatin, Solid Lipid nanoparticles, zeta potential, Particle size, Transmission electron Microscopy.

Complete cure of a patient with HBV-associated hepatocellular carcinoma with lung metastasis using interferon and survival up to 108 months: A case report and literature review.

Hepatocellular carcinoma (HCC) has a poor prognosis due to its asymptomatic onset and susceptibility to metastasis. The survival of patients with advanced HCC is 6–12 months. As a first-line medicine for the control of hepatitis B virus, interferon (IFN) is also capable of inhibiting tumor growth and modulating immunity. However, treatment of HCC with lung metastasis using IFN has been rarely reported. The present study reports the case of one patient with HCC having lung metastasis who underwent a one-time treatment with transcatheter arterial chemoembolization (TACE) and was subsequently completely cured by single peginterferon α 2a (PEG-IFNα2a); and has survived up to 108 months. A 53-year-old male patient diagnosed with HBV-related HCC with lung metastasis underwent TACE using floxuridine (FUDR) 500 mg, cisdiamine dichloroplatinum (CDDP) 20 mg, mitomycin 10 mg, and ultrafluid lipiodol 10 ml, together with local thoracic aorta chemotherapy using FUDR 250 mg and CDDP 20 mg. His metastatic lung cancer aggravated. However, after 9 months of treatment with subcutaneous injections of PEG-IFNα 2a once per week, the metastatic lung foci gradually shrunk until disappearance and the HCC lesion stabilized without progression. According to the World Health Organization criteria for the efficacy of solid tumors, this was a case of complete response. Upon follow-up up to 108 months his metastatic lung cancer had disappeared and HCC did not recur. Therefore, IFN intervention may be an appropriate novel adjuvant therapy for patients with HCC with lung metastasis and requires further attention and study.

P-16 - Role of peroxiredoxins in the development of drug resistance in cancer cells

Peroxiredoxins (Prxs) regulate cell signaling and proliferation, protect protein structure and inhibit redox-dependent pathways of apoptosis activation, which attests to their important role in cell protection from oxidative stress. Here we studied the role of Prxs in the formation of cancer cell resistance to cisplatin (cis-diamine dichloroplatinum, CDDP); its cytotoxic effect, apart from alkylating mechanism, is associated with activation of ROS generation. It was found that drug resistance formation was accompanied by a significant increase in the expression of PRDX1, PRDX3, PRDX6 genes in human mammary adenocarcinoma (MCF -7/CDDP) and ovarian carcinoma (SKOV-3/CDDP) cells. A more pronounced rise was noted for Prx6 mRNA. It is known that oxidized forms of Prx1 and Prx3 are reduced by thioredoxin1 (Trx1) while glutathione repairs the oxidized Prx6. Our study found that siRNA knockdown of Trx1 increased CDDP-induced death of resistant cells which was significantly rose under additively using of siRNA knockdown of Prx6. It can be concluded that the data obtained confirm the important contribution of Prxs into redox-dependent mechanisms in the development of cancer cell resistance to CDDP. The publication was prepared with the support of the “RUDN University Program 5–100”.

The antitumor effect of folic acid conjugated-Auricularia auricular polysaccharide-cisplatin complex on cervical carcinoma cells in nude mice

A tumor-targeted, folic acid (FA) conjugated-Auricularia auricular polysaccharide (AAP) -cis-diaminedichloroplatinum (CDDP) complex (FA-AAP-CDDP) was used for cervical carcinoma chemotherapy. The drug delivery system was able to enhance the antitumor potency of CDDP, and to reduce the toxic side effects of CDDP. The kidney of mice treated by FA-AAP-CDDP complex had higher superoxide dismutase, catalase, and glutathione peroxidase activities, and lower malondialdehyde. FA-AAP-CDDP complex could induce more interleukin-2, interleukin-4, and interferon-γ in mice. In addition, the FA-AAP-CDDP complex significantly promoted the expression of Bax and caspase-3 protein, but inhibited the expression of Bcl-2 protein, which activated the mitochondrial apoptotic pathway of tumor cells in nude mice. Moreover, the FA-AAP-CDDP complex had a higher intratumoral accumulation, was lower in the kidneys. This study may provide a new direction for folate receptor targeted polymers to improve anti-tumor activity, but reduce side effects of CDDP.

Identification and characterisation of lamprey protein kinase C delta-like gene

Protein kinase C-δ (PKC-δ), a member of the lipid-regulated serine/threonine PKC family, has been implicated in a wide range of important cellular processes, such as cell growth, differentiation, and apoptosis. Lampreys belong to the most primitive class of vertebrates, and there is little information on PKC-δ in these animals. In this study, a PKC-δ-like cDNA sequence and deduced PKC-δ-like amino acid sequence were identified in the Japanese lamprey (Lampetra japonica). The PKC-δ-like gene shared approximately 60% sequence identity with its homologs in jawed vertebrates. The anti-PKC-δ-like polyclonal antibodies were well prepared, and experiments showed that PKC-δ-like was primarily distributed in the supraneural body of the lamprey. Both mRNA and protein levels of PKC-δ-like in supraneural body cells were increased after incubation with cis-diaminedichloroplatinum (CDDP). Moreover, PKC-δ-like protein induced the apoptosis of HEK-293T cells. In addition, the activation of PKC-δ-like resulted in apoptosis. Conversely, the inhibition of PKC-δ-like activity disrupted the CDDP-mediated induction of cellular apoptosis. These results indicate that PKC-δ-like identified in lampreys might play an important role in apoptosis in jawless vertebrates.

P 052 - Thioredoxins, glutaredoxins and peroxiredoxins in redox-dependent formation of cancer cell resistance

Thioredoxin (Trx), glutaredoxin (Grx), peroxiredoxin (Prx) which can play significant role in adaptation to oxidative stress and in maintaince of cell proteostasis. Aims Here we studied the expression of Trx, Grx and Prx isoforms under the formation of cancer cell resistance to cisplatin (cis-diamine dichloroplatinum, CDDP); its cytostatic effect, apart from alkylating mechanism, is associated with activation of generation of reactive oxygen species. Results Under development of resistance of human mammary adenocarcinoma (MCF-7/CDDP) and ovarian carcinoma (SKOV-3/CDDP) cells to CDDP co-ordinative enhanced expression of genes encoding isoforms of Trx (TRX1,TRX2), Grx (GLRX1, GLRX2), Prx (PRDX1, PRDX2, PRDX3, PRDX6) was found in both types of resistant cells in compare with wild cells. Decrease of growth of apoptotic cell death was observed under exposure to hydrogen peroxide in the CDDP-resistant cells which possessed elevated antioxidant status, as evidenced by the high level of GSH/GSSG and low generation of ROS. There was a much smaller increase in the level of phosphorylated forms of ASK1 and JNK1 in the resistant cells of each line compared with the sensitive cells. It can be concluded that the data obtained confirm the important contribution of Trxs, Grxs, Prxs into redox-dependent mechanisms for the development of cancer cells resistance to CDDP.

Delayed sodium thiosulphate administration reduces cisplatin efficacy on mouse EMT6 tumour cells in vitro.

To determine whether simultaneous and/or delayed administration of sodium thiosulphate (STS) affects the oncologic effect of cisplatin or cisdiaminedichloroplatinum (CDDP) in EMT6 tumour cells in vitro. Cell biology research laboratory. Clonogenic assays of EMT6 tumour cells with CDDP alone, CDDP plus simultaneous STS, and CDDP plus a 4-hour delay of STS were performed. Growth fractions under these three conditions were compared. Tumour growth was statistically significantly increased when CDDP and STS were administered compared with CDDP alone. There was no statistically significant difference between simultaneous and 4-hour delay of STS administration. We conclude that in EMT6 cells, either simultaneous administration or a 4-hour delay of STS administration significantly decreases CDDP efficacy. STS adversely affects CDDP's oncologic efficacy in EMT6 cell cultures in vitro.

Overexpression of ABCC3 promotes cell proliferation, drug resistance, and aerobic glycolysis and is associated with poor prognosis in urinary bladder cancer patients.

Human urinary bladder cancer (UBC) is the one of the most common malignancies worldwide and occurs at a higher frequency in male individuals. ATP-binding cassette, subfamily C, member 3 (ABCC3), a member of the ABC transporter family, is highly expressed in tumor cells, where it actively effluxes a broad spectrum of metabolites. However, the expression and role of ABCC3 in human UBC remains unclear. Our study aimed to identify the expression status of ABCC3 in UBC cases and investigate the biological effects on UBC in cells. We found that both mRNA and protein levels of ABCC3 were significantly higher in UBC tissues than normal tissues. Immunochemistry evaluation of ABCC3 expression in 122 UBC clinical specimens showed that high expression of ABCC3 had a positive correlation with UBC tumor size, advanced tumor node metastasis stage, and malignant histology. Moreover, high ABCC3 expression was linked to poor overall survival in UBC. ABCC3 effects on cell proliferation and drug resistance were measured by colony formation and methylthiazolyldiphenyl-tetrazolium bromide (MTT) assays. ABCC3-knockdown cells showed a significant decrease in cell growth and drug resistance. RNA interference of ABCC3 also caused downregulation of lactate dehydrogenase A (LDHA), which positively correlated with ABCC3 expression in UBC specimens. In addition, cancer cell glycolytic ability was decreased upon ABCC3 knockdown. The activity of LDHA was also abrogated in ABCC3-deficient UBC cells, and the blockade of LDHA increased UBC cells sensitivity to Cis-diamine dichloroplatinum (CDDP). In summary, our study suggests ABCC3 is an important oncoprotein involved in glycolysis and drug resistance. These data also indicates that ABCC3 could be a potential prognostic marker and promising therapeutic target in UBC.

Dissociation of E-cadherin/β-catenin complex by MG132 and bortezomib enhances CDDP induced cell death in oral cancer SCC-25 cells

E-cadherin/β-catenin complex plays an important role in maintaining the homeostasis of tissues and regulating cell proliferation, survival and apoptosis. To address the relationships between the change of E-cadherin/β-catenin complex and cell apoptosis, human oral squamous carcinoma SCC-25 cells were used to investigate whether the dissociation of the E-cadherin/β-catenin complex was the main reason of MG132- or bortezomib-induced apoptosis. We found that MG132 or bortezomib alone induced remarkable loss of cell integrity and contact, inhibited cell growth, survival, migration and caused cell cycle arrest, intracellular ROS production. Further experiments showed that colony formations were significantly decreased by MG132 and bortezomib alone or plus cis-diaminedichloroplatinum (CDDP). Immunofluorescence staining showed that SCC-25 cells exhibited remarkable accumulations of β-catenin in cytoplasm and few E-cadherin in cell membranes after MG132 or bortezomib treatment. Western blot results showed that MG132 or bortezomib induced high accumulation of ubiquitinated proteins and activation of apoptosis related protein caspase-3. Meanwhile, the combinational use of MG132 or bortezomib with CDDP led to synergistic effects on SCC-25 cells. However, knockdown of β-catenin could decrease MG132 or bortezomib induced cell death. Taken together, our data suggest that the regulation of E-cadherin/β-catenin complex could be a promising therapeutic target to overcome the multidrug resistance of oral cancer.

Liquiritigenin Potentiates the Inhibitory Effects of Cisplatin on Invasion and Metastasis Via Downregulation MMP-2/9 and PI3 K/AKT Signaling Pathway in B16F10 Melanoma Cells and Mice Model

Liquiritigenin (LQ) is a flavanone extracted from glycyrrhizae. Previous studies have demonstrated that LQ possesses antimigration properties in HELA and A549 cells. The present research, as an extension of our earlier ones, investigated whether LQ can enhance the antimigration and antiinvasion effect of cis-diamine dichloroplatinum (CDDP) in B16F10 melanoma cell. The data indicated that LQ (25, 50, 100, 200 μM) combined with CDDP (2 μM) significantly reduced B16F10 cell viability compared to CDDP (2 μM)-treated only. The different doses of LQ combined with CDDP significantly suppressed cell migration (21.5%, 49.6%, 75.6%) and cell invasion (26.2%, 51.4%, 69.5%) compared with CDDP-treated alone, suggesting that LQ enhance the inhibition action of CDDP on cell migration and invasion. Moreover, LQ/CDDP combination led to the downregulation of protein expression of MMP-2/9, PI3 K, p-AKT, and upregulated PTEN protein level that play an important role in tumor metastasis progression. Further study demonstrated the enhancement effect of LQ on CDDP suppressing lung metastasis in a mice model being inoculated by the B16F10 melanoma cells. In conclusion, the results suggested that LQ plays an intensive role on CDDP suppressing invasion and metastasis through regulating the PI3 K/AKT signal pathway and suppressing the protein expression of MMP-2/9.

MiR-101 sensitizes A549 NSCLC cell line to CDDP by activating caspase 3-dependent apoptosis

MicroRNA-101 (miR-101) is evidently downregulated in several types of cancer, including non-small cell lung cancer (NSCLC), and is crucial in sensitizing cells to chemotherapy drugs. The aim of the present study was to investigate the correlation between miR-101 and chemosensitivity in the A549 NSCLC cell line. Here, we used the human A549 cell line for transfection with an miR-101 overexpressing vector and detected the cytotoxic acticity, proliferation and apoptosis of cis-diaminedichloroplatinum (CDDP) in A549-miR-101 and A549-mock cells. We demonstrated that overexpression of miR-101 sensitized A549 cells to CDDP, one of the most frequently used agents in curing or controlling NSCLC and enhanced CDDP-induced cell death and caspase 3-dependent apoptosis. In addition, miR-101 facilitated the inhibitory role of CDDP in A549 cell colony formation. Overall, the results of the present study demonstrated that miR-101 sensitizes the A549 NSCLC cell line to CDDP via the activation of caspase 3-dependent apoptosis.

MicroRNA‐21 increases the resistance to CDDP in Hela cervical carcinoma cells by targeting PDCD4 and MSH2

ObjectivesMicroRNA‐21 (miR‐21) has been found to be over‐expressed in many human cancers, including cervical cancer. Our aim is to investigate the association of miR‐21 with the chemosensitivity of HeLa cervical carcinoma cells to cis‐Diaminedichloroplatinum (CDDP).MethodsWith cervical carcinoma cell lines, HeLa and CDDP‐resistant HeLa (HeLa/CDDP), the cell growth was examined by MTT assays with miR‐21 or miR‐21 inhibitor transfection. TaqMan RT‐PCR was performed to detect the miR‐21 and mRNA expression of Programmed Cell Death 4 (PDCD4) and mutS homolog 2, colon cancer, nonpolyposis type 1 (MSH2). The protein expression of PDCD4 and MSH2 was detected with western blot assay. Luciferase assay was performed to analyze the potential targets of miR‐21.ResultsCell growth results suggested miR‐21 inhibitor inhibit CDDP‐resistant HeLa growth significantly. Compared with HeLa, MiR‐21 and mRNA of PDCD4 and MSH2 expression in HeLa/CDDP were higher, but the protein expression of PDCD4 and MSH2 in HeLa/CDDP were downregulated in western blot results. Transfection of miR‐21 inhibitor for HeLa/CDDP with PDCD4 3′ untranslated region (3′ UTR) or MSH2 3′UTR vector showed significant increase in luciferase activity compared with control.ConclusionsOver‐expression of miR‐21 may play critical roles for the CDDP‐resistance in cervical cancer, at least in part via targeting PDCD4 and MSH2.

1.2.2.Synthesis, crystal structure and in vitro anti-tumor activity of dibutyltin complex of 2,4-dichloro-5-fluorobenzoic acid

The dibutyltin complex of 2,4-dichloro-5- fluorobenzoic acid, [(2,4-Cl 2 -5-FC 6 H 2 C(O)OSnBu 2 ) 2 O] 2 (Bu = CH 2 CH 2 CH 2 CH 3 ) ( 1 ), has been synthesized and characterized by elemental analysis, FT-IR, 119 Sn NMR spectroscopy, and Xray single crystal diffraction. Compound 1 is a centrosymmetric dimmer with two distinct types of carboxylate moieties and tin atoms with distorted trigonal bipyramidal geometries. The in vitro anti-tumor activity of 1 against two human tumor cell lines was found to be higher than that for cis-platin [cis diaminedichloroplatinum( II)] used clinically. Supporting information : FT-IR, 119 Sn NMR, X-Ray, Proliferation inhibitory rate, Cif file.