Sensitivity to Cisplatin in Head and Neck Cancer Cells Is Significantly Affected by Patient-Derived Cancer-Associated Fibroblasts

Cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor stroma. CAFs can impact many important steps of cancerogenesis and may also influence treatment resistance. Some of these effects need the direct contact of CAFs and cancer cells, while some involve paracrine signals. In this study, we investigated the ability of head and neck squamous cell carcinomas (HNSCC) patient-derived CAFs to promote or inhibit the colony-forming ability of HNSCC cells. The effect of cisplatin on this promoting or inhibiting influence was also studied. The subsequent analysis focused on changes in the expression of genes associated with cancer progression. We found that cisplatin response in model HNSCC cancer cells was modified by coculture with CAFs, was CAF-specific, and different patient-derived CAFs had a different “sensitizing ratio”. Increased expression of VEGFA, PGE2S, COX2, EGFR, and NANOG in cancer cells was characteristic for the increase of resistance. On the other hand, CCL2 expression was associated with sensitizing effect. Significantly higher amounts of cisplatin were found in CAFs derived from patients who subsequently experienced a recurrence. In conclusion, our results showed that CAFs could promote and/or inhibit colony-forming capability and cisplatin resistance in HNSCC cells via paracrine effects and subsequent changes in gene expression of cancer-associated genes in cancer cells.     

Sensitization of MCF7 Cells with High Notch1 Activity by Cisplatin and Histone Deacetylase Inhibitors Applied Together

Histone deacetylase inhibitors (HDIs) are promising anti-cancer agents that inhibit proliferation of many types of cancer cells including breast carcinoma (BC) cells. In the present study, we investigated the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two HDIs, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), in luminal-like BC cells. The type of drug–drug interaction between CDDP and HDIs was determined by isobolographic analysis. MCF7 cells were genetically modified to express differential levels of Notch1 activity. The cytotoxic effect of SAHA or VPA was higher on cells with decreased Notch1 activity and lower for cells with increased Notch1 activity than native BC cells. The isobolographic analysis demonstrated that combinations of CDDP with SAHA or VPA at a fixed ratio of 1:1 exerted additive or additive with tendency toward synergism interactions. Therefore, treatment of CDDP with HDIs could be used to optimize a combined therapy based on CDDP against Notch1-altered luminal BC. In conclusion, the combined therapy of HDIs and CDDP may be a promising therapeutic tool in the treatment of luminal-type BC with altered Notch1 activity.     

牛磺酸对顺铂引起的小鼠肾髓质ATP酶活性变化的影响

目的 :探讨牛磺酸对顺铂引起的小鼠肾髓质ATP酶活性的影响 ;方法 :4 0只小鼠随机分为正常对照组、CDDP组、牛磺酸 2 0 0mg组 (Tau2 0 0 )和牛磺酸 4 0 0mg组 (Tau4 0 0 ) ,分取肾髓质、制备匀浆 ,用生化法测定Na ,K -ATP酶、Ca2 -ATP酶和Mg2 -ATP酶活性 ;结果 :CDDP组、Tau2 0 0组、Tau4 0 0组肾髓质Na ,K -ATP酶、Ca2 -ATP酶和Mg2 -ATP酶活性均明显低于正常对照组 (P <0 .0 1)。Tau2 0 0组、Tau4 0 0组肾髓质Na ,K -ATP酶和Ca2 -ATP酶活性均明显高于CDDP组 (P <0 .0 1或P <0 .0 5 ) ,而Mg2 -ATP酶活性与CDDP组相比无显著差别 (P >0 .0 5 ) ;结论 :牛磺酸可明显增加肾髓质Na ,K -ATP酶和Ca2 -ATP酶活性 ,对顺铂引起的肾毒性具有防治作用。     

Protective Effect of Polysaccharides Extracted from Cudrania tricuspidata Fruit against Cisplatin-Induced Cytotoxicity in Macrophages and a Mouse Model

Although cisplatin is one of most effective chemotherapeutic drugs that is widely used to treat various types of cancer, it can cause undesirable damage in immune cells and normal tissue because of its strong cytotoxicity and non-selectivity. This study was conducted to investigate the cytoprotective effects of Cudrania tricuspidata fruit-derived polysaccharides (CTPS) against cisplatin-induced cytotoxicity in macrophages, lung cancer cell lines, and a mouse model, and to explore the possibility of application of CTPS as a supplement for anticancer therapy. Both cisplatin alone and cisplatin with CTPS induced a significant cytotoxicity in A549 and H460 lung cancer cells, whereas cytotoxicity was suppressed by CTPS in cisplatin-treated RAW264.7 cells. CTPS significantly attenuated the apoptotic and necrotic population, as well as cell penetration in cisplatin-treated RAW264.7 cells, which ultimately inhibited the upregulation of Bcl-2-associated X protein (Bax), cytosolic cytochrome c, poly (adenosine diphosphateribose) polymerase (PARP) cleavage, and caspases-3, -8, and -9, and the downregulation of B cell lymphoma-2 (Bcl-2). The CTPS-induced cytoprotective action was mediated with a reduction in reactive oxygen species production and mitochondrial transmembrane potential loss in cisplatin-treated RAW264.7 cells. In agreement with the results obtained above, CTPS induced the attenuation of cell damage in cisplatin-treated bone marrow-derived macrophages (primary cells). In in vivo studies, CTPS significantly inhibited metastatic colonies and bodyweight loss as well as immunotoxicity in splenic T cells compared to the cisplatin-treated group in lung metastasis-induced mice. Furthermore, CTPS decreased the level of CRE and BUN in serum. In summation, these results suggest that CTPS-induced cytoprotective action may play a role in alleviating the side effects induced by chemotherapeutic drugs.     

The Application of Biomaterials in the Treatment of Platinum-Resistant Ovarian Cancer

More than 70 % of women with ovarian cancer are diagnosed with advanced-stage disease, which is initially treated with cytoreductive surgery, and combination chemotherapy with platinum-based compounds. Most patients initially respond to platinum-based therapy, but eventually up to 80 % of this responsive cohort becomes refractory due to the development of platinum resistance. This review discusses current and potential therapeutic approaches that exploit biomaterial-based applications to combat platinum resistance either by enhancing the delivery of platinum-based drugs or prodrugs, delivering other toxic non-platinum-based bioactive factors (by themselves or in combination with platinum-based drugs) or by delivering other bioactive factors that re-sensitize resistant ovarian cancer cells to these drugs. The types of materials that are used, the bioactive factors applied (i.e., drug or gene delivery), and the specific agents that are employed to target these types of cancer cells are discussed. We conclude that the unique attributes of biomaterial-based applications can be further explored toward overcoming platinum-resistant ovarian cancer as monotherapy, or in combination with other treatment strategies.     

顺铂联合长春瑞滨同步放化疗治疗局部晚期非小细胞肺癌的长期疗效

目的 探讨顺铂联合长春瑞滨（NP方案）同步放疗治疗局部晚期非小细胞肺癌的长期疗效及毒副作用.方法 随访57例NP方案同步放化疗病例.NP方案为长春瑞滨25 mg·m-2,第1、8天;顺铂25 mg·m-2第1-3天,21 d为1个周期.放疗采用适形放疗,总剂量为60～70 Gy,6～7周完成放疗.同步放化疗于放疗第1天开始,放疗期间共行2个周期化疗,放疗结束后继续接受2个周期化疗.观察治疗后1、3、5年的无复发生存期（PFS）和总生存期（OS）及晚期毒副作用（肺毒性、食管毒性）.结果 同步放化疗后客观缓解率为80.7%,1、3、5年无进展生存率为51.8%、22.2%、16.7%,相应的总生存率为80.5%、37.3%和21.0%;中位无进展生存时间、总生存时间分别为12.8和29.9个月.1级、2级、3级晚期肺毒副作用分别为14例、12例、5例,无4级和5级晚期肺毒副作用,26例（45.6%）未见晚期毒副作用.晚期食管毒副作用3例,均为1级反应,无2级以上食管晚期毒副作用.结论 顺铂联合长春瑞滨同步放化疗治疗局部晚期非小细胞肺癌的长期疗效显著,且毒副作用可耐受.     

Comparative Cytotoxicity of Artemisinin and Cisplatin and Their Interactions with Chlorogenic Acids in MCF7 Breast Cancer Cells

In parts of Africa and Asia, self‐medication with a hot water infusion of Artemisia annua (Artemisia tea) is a common practice for a number of ailments including malaria and cancer. In our earlier work, such an extract showed better potency than artemisinin alone against both chloroquine‐sensitive and ‐resistant parasites. In this study, in vitro tests of the infusion in MCF7 cells showed high IC₅₀ values (>200 μM ). The combination of artemisinin and 3‐caffeoylquinic acid (3CA), two major components in the extract, was strongly antagonistic and gave a near total loss of cytotoxicity for artemisinin. We observed that the interaction of 3CAs with another cytotoxic compound, cisplatin, showed potentiation of activity by 2.5‐fold. The chelation of cellular iron by 3CA is hypothesized as a possible explanation for the loss of artemisinin activity.     

Pericytes of Stria Vascularis Are Targets of Cisplatin-Induced Ototoxicity: New Insights into the Molecular Mechanisms Involved in Blood-Labyrinth Barrier Breakdown

The stria vascularis (SV) contributes to cochlear homeostasis and consists of three layers, one of which contains the blood-labyrinthic barrier (BLB), with a large number of bovine cochlear pericytes (BCPs). Cisplatin is a chemotherapeutic drug that can damage the SV and cause hearing loss. In this study, cell viability, proliferation rate, cytotoxicity and reactive oxygen species production were evaluated. The protein content of phospho-extracellular signal-regulated kinases (ERK) 1/2, total ERK 1/2, phospho-cytosolic phospholipase A₂ (cPLA₂), total cPLA₂ and cyclooxygenase 2 (COX-2) and the release of prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) from BCPs were analyzed. Finally, the protective effect of platelet-derived growth factor (PDGF-BB) on BCPs treated with cisplatin was investigated. Cisplatin reduced viability and proliferation, activated ERK 1/2, cPLA₂ and COX-2 expression and increased PGE2 and VEGF release; these effects were reversed by Dexamethasone. The presence of PDGF-BB during the treatment with cisplatin significantly increased the proliferation rate. No studies on cell regeneration in ear tissue evaluated the effect of the PDGF/Dex combination. The aim of this study was to investigate the effects of cisplatin on cochlear pericytes and propose new otoprotective agents aimed at preventing the reduction of their vitality and thus maintaining the BLB structure.