Mechanisms underlying acquired platinum resistance in high grade serous ovarian cancer - a mini review

Background

Advanced epithelial ovarian cancer is one of the hardest human malignancies to treat. Standard treatment involves cytoreductive surgery and platinum-based chemotherapy, however, median progression-free survival for patients diagnosed with advanced stage disease (FIGO stages III and IV) is approximately 18?months. There has been little improvement in overall survival over the past decade and less than half of women with advanced stage disease will be living 5?years after diagnosis. A majority of patients initially have a favourable response to platinum-based chemotherapy, but most will eventually relapse and their disease will become platinum resistant.

Inhibition of PI3K increases oxaliplatin sensitivity in cholangiocarcinoma cells

Background  

Resistance of cholangiocarcinoma to chemotherapy is a major problem in cancer treatment. The mechanism of resistance is believed to involve phosphoinositide-3- kinase (PI3K)/Akt activation. Although the platinum-containing compound oxaliplatin has been extensively used in the treatment of several solid tumors, recent data regarding its use to treat cholangiocarcinoma are ambiguous. Oxaliplatin resistance in this disease could potentially involve PI3K pathways. We, therefore, examined the effects of PI3K pathways in cholangiocarcinoma cells in modulating oxaliplatin resistance.     

The scavenging of superoxide radicals promotes apoptosis induced by a novel cell-permeable fusion protein,sTRAIL:FeSOD,in tumor necrosis factor-related apoptosis-inducing ligand-resistant leukemia cells

Background  

Many cancer cells develop resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, necessitating combination with chemotherapy, and normal cells manifest side effects due to the combined treatment regimen of TRAIL and chemotherapeutic drugs. A novel cancer therapy utilizing TRAIL is thus urgently needed.     

<Emphasis Type="Italic">In Silico</Emphasis> Quantitative Structure-Activity Relationship Studies on P-gp Modulators of Tetrahydroisoquinoline-Ethyl-Phenylamine Series

Background  

Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. The drug efflux by a transport protein is the main reason for MDR. In humans, MDR mainly occurs when the ATP-binding cassette (ABC) family of proteins is overexpressed simultaneously. P-glycoprotein (P-gp) is most commonly associated with human MDR; it utilizes energy from adenosine triphosphate (ATP) to transport a number of substrates out of cells against concentration gradients. By the active transport of substrates against concentration gradients, intracellular concentrations of substrates are decreased. This leads to the cause of failure in cancer chemotherapy.     

Lowering the apoptotic threshold in colorectal cancer cells by targeting mitochondria

Background  

Colorectal cancer is the third most-common cancer and the second most-common cause of cancer related death in UK. Although chemotherapy plays significant role in the treatment of colorectal cancer, morbidity and mortality due to drug resistance and cancer metastasis are yet to be eliminated. Recently, doxycycline has been reported to have cytotoxic and anti-proliferating properties in various cancer cells. In this study, whether doxycycline was apoptosis threshold lowering agent in colorectal cancer cells by targeting mitochondria was answered.     

Hypoxia and TGF-β1 lead to endostatin resistance by cooperatively increasing cancer stem cells in A549 transplantation tumors

Background

Lung cancer is the leading cause of cancer-related deaths worldwide, and treatments for lung cancer have a high failure rate. Anti-angiogenic therapy is also often ineffective because of refractory disease. Endostatin (ES) is one of the most widely-used anti-angiogenic drugs for lung cancer in China, and resistance to it is a barrier that needs to be resolved. It has been shown that myeloid-derived suppressor cells (MDSCs) are involved in resistance to ES. Whether other cells and/or cell factors in the tumor microenvironment that have been shown to be related to resistance to other anti-cancer drugs are also involved in ES resistance is unknown.

Results

In this study, we showed that after continuously treatment with ES for 12 days, volumes of A549 transplantation tumors of mice reached the sizes of tumors which were borne by mice that were treated with normal saline and this meant that resistance to ES appeared. Cancer stem cells (CSCs), which have been widely accepted as one of reasons responsible for resistance to many anti-tumor drugs were also being discovered increased proportionally in A549 transplantation tumors after ES treatment for 12 days. During further exploration of reasons for this increase, we discovered that after ES treatment, microvessel density and vascular endothelial growth factor level was decreased in tumors, whereas transforming growth factor (TGF)-β1 level was elevated, and MDSCs, one of the sources of TGF-β1, were also increased. We speculate that hypoxia and TGF-β1 are responsible for the increased CSC number in A549 transplantation tumors. By using cobalt chloride to mimic hypoxia and human recombinant TGF-β1 in vitro, we found that hypoxia and TGF-β1can indeed enhance the stemness of A549 cells. In addition, the inductive effect of hypoxia is stronger than TGF-β1, and the combination of both is stronger than either alone, which is first report of such a finding, to our knowledge.

Conclusions

Increased TGF-β1 and strengthened hypoxia in A549 transplantation tumors, as a result of ES therapy, cooperatively increase proportion of CSCs that are involved in ES resistance which was revealed by failure of tumor volume repression after continuously treatment with ES for 12 days.

     

ncRNAs associated with drug resistance and the therapy of digestive system neoplasms

Digestive system cancer remains a common cancer and the main cause of cancer-related death worldwide. Drug resistance is a major challenge in the therapy of digestive system cancer, and represents a primary obstacle in the treatment of cancer by restricting the efficiency of both traditional chemotherapy and biological therapies. Existing studies indicate that noncoding RNAs play an important role in the evolution and progression of drug resistance in digestive system cancer, mainly by modulating drug transporter-related proteins, DNA damage repair, cell-cycle-related proteins, cell apoptosis-related proteins, drug target-related proteins, and the tumor microenvironment. In this review, we address the potential mechanisms of ncRNAs underlying drug resistance in digestive system tumors and discuss the possible application of ncRNAs against drug resistance in digestive system tumors.     

A new stochastic and state space model of human colon cancer incorporating multiple pathways

Background and Purpose  

Studies by molecular biologists and geneticists have shown that tumors of human colon cancer are developed from colon stem cells through two mechanisms: The chromosomal instability and the micro-satellite instability. The purpose of this paper is therefore to develop a new stochastic and state space model for carcinogenesis of human colon cancer incorporating these biological mechanisms.     

Doxorubicin-induced ovarian toxicity

Background  

Young cancer patients may occasionally face infertility and premature gonadal failure. Apart from its direct effect on follicles and oocytes, chemotherapy may induce ovarian toxicity via an impact on the entire ovary. The role of doxorubicin in potential ovarian failure remains obscure. Our intention was to elucidate doxorubicin-related toxicity within ovaries.     

Pharmacologic modulation of serine/threonine phosphorylation highly sensitizes PHEO in a MPC cell and mouse model to conventional chemotherapy

Background

The failure of cytotoxic cancer regimens to cure the most drug-resistant, well-differentiated solid tumors has been attributed to the heterogeneity of cell types that differ in their capacities for growth, differentiation, and metastases. We investigated the effect of LB1, a small molecule inhibitor of serine/threonine protein phosphatase 2A (PP2A), on its ability to inhibit a low growth fraction and highly drug-resistant solid neuroendocrine tumor, such as metastatic pheochromocytoma (PHEO). Subsequently, we evaluated the increased efficacy of chemotherapy combined with LB1.

Methodology/Principal Findings

The effect of LB1 and temozolomide (TMZ), a standard chemotherapeutic agent that alone only transiently suppressed the growth and regression of metastatic PHEO, was evaluated in vitro on a single PHEO cell line and in vivo on mouse model of metastatic PHEO. In the present study, we show that metastatic PHEO, for which there is currently no cure, can be eliminated by combining LB1, thereby inhibiting PP2A, with TMZ. This new treatment approach resulted in long term, disease-free survival of up to 40% of animals bearing multiple intrahepatic metastases, a disease state that the majority of patients die from. Inhibition of PP2A was associated with prevention of G1/S phase arrest by p53 and of mitotic arrest mediated by polo-like kinase 1 (Plk-1).

Conclusions/Significance

The elimination of DNA damage-induced defense mechanisms, through transient pharmacologic inhibition of PP2A, is proposed as a new approach for enhancing the efficacy of non-specific cancer chemotherapy regimens against a broad spectrum of low growth fraction tumors very commonly resistant to cytotoxic drugs.     

miRNA signature associated with outcome of gastric cancer patients following chemotherapy

Background

Resistance to chemotherapy severely limits the effectiveness of chemotherapy drugs in treating cancer. Still, the mechanisms and critical pathways that contribute to chemotherapy resistance are relatively unknown. This study elucidates the chemoresistance-associated pathways retrieved from the integrated biological interaction networks and identifies signature genes relevant for chemotherapy resistance.

Methods

An integrated network was constructed by collecting multiple metabolic interactions from public databases and the k-shortest path algorithm was implemented to identify chemoresistant related pathways. The identified pathways were then scored using differential expression values from microarray data in chemosensitive and chemoresistant ovarian and lung cancers. Finally, another pathway database, Reactome, was used to evaluate the significance of genes within each filtered pathway based on topological characteristics.

Results

By this method, we discovered pathways specific to chemoresistance. Many of these pathways were consistent with or supported by known involvement in chemotherapy. Experimental results also indicated that integration of pathway structure information with gene differential expression analysis can identify dissimilar modes of gene reactions between chemosensitivity and chemoresistance. Several identified pathways can increase the development of chemotherapeutic resistance and the predicted signature genes are involved in drug resistant during chemotherapy. In particular, we observed that some genes were key factors for joining two or more metabolic pathways and passing down signals, which may be potential key targets for treatment.

Conclusions

This study is expected to identify targets for chemoresistant issues and highlights the interconnectivity of chemoresistant mechanisms. The experimental results not only offer insights into the mode of biological action of drug resistance but also provide information on potential key targets (new biological hypothesis) for further drug-development efforts.     

Markers of tumor-initiating cells predict chemoresistance in breast cancer

Purpose

Evidence is lacking whether the number of breast tumor-initiating cells (BT-ICs) directly correlates with the sensitivity of breast tumors to chemotherapy. Here, we evaluated the association between proportion of BT-ICs and chemoresistance of the tumors.

Methods

Immunohistochemical staining(IHC) was used to examine the expression of aldehyde dehydrogenase 1 (ALDH1) and proliferating cell nuclear antigen, and TUNEL was used to detect the apoptosis index. The significance of various variables in patient survival was analyzed using a Cox proportional hazards model. The percentage of BT-ICs in breast cancer cell lines and primary breast tumors was determined by ALDH1 enzymatic assay, CD44⁺/CD24⁻ phenotype and mammosphere formation assay.

Results

ALDH1 expression determined by IHC in primary breast cancers was associated with poor clinical response to neoadjuvant chemotherapy and reduced survival in breast cancer patients. Breast tumors that contained higher proportion of BT-ICs with CD44⁺/CD24⁻ phenotype, ALDH1 enzymatic activity and sphere forming capacity were more resistant to neoadjuvant chemotherapy. Chemoresistant cell lines AdrR/MCF-7 and SK-3rd, had increased number of cells with sphere forming capacity, CD44⁺/CD24⁻ phenotype and side-population. Regardless the proportion of T-ICs, FACS-sorted CD44⁺/CD24⁻ cells that derived from primary tumors or breast cancer lines were about 10–60 fold more resistant to chemotherapy relative to the non- CD44⁺/CD24⁻ cells and their parental cells. Furthermore, our data demonstrated that MDR1 (multidrug resistance 1) and ABCG2 (ATP-binding cassette sub-family G member 2) were upregulated in CD44⁺/CD24⁻ cells. Treatment with lapatinib or salinomycin reduced the proportion of BT-ICs by nearly 50 fold, and thus enhanced the sensitivity of breast cancer cells to chemotherapy by around 30 fold.

Conclusions

These data suggest that the proportion of BT-ICs is associated with chemotherapeutic resistance of breast cancer. It highlights the importance of targeting T-ICs, rather than eliminating the bulk of rapidly dividing and terminally differentiated cells, in novel anti-cancer strategies.     

Circulating MiR-125b as a marker predicting chemoresistance in breast cancer

Background

Chemotherapy is an important component in the treatment paradigm for breast cancers. However, the resistance of cancer cells to chemotherapeutic agents frequently results in the subsequent recurrence and metastasis. Identification of molecular markers to predict treatment outcome is therefore warranted. The aim of the present study was to evaluate whether expression of circulating microRNAs (miRNAs) can predict clinical outcome in breast cancer patients treated with adjuvant chemotherapy.

Methodology/Principal Findings

Circulating miRNAs in blood serum prior to treatment were determined by quantitative Real-Time PCR in 56 breast cancer patients with invasive ductal carcinoma and pre-operative neoadjuvant chemotherapy. Proliferating cell nuclear antigen (PCNA) immunostaining and TUNEL were performed in surgical samples to determine the effects of chemotherapy on cancer cell proliferation and apoptosis, respectively. Among the miRNAs tested, only miR-125b was significantly associated with therapeutic response, exhibiting higher expression level in non-responsive patients (n = 26, 46%; p = 0.008). In addition, breast cancers with high miR-125b expression had higher percentage of proliferating cells and lower percentage of apoptotic cells in the corresponding surgical specimens obtained after neoadjuvant chemotherapy. Increased resistance to anticancer drug was observed in vitro in breast cancer cells with ectopic miR-125b expression; conversely, reducing miR-125b level sensitized breast cancer cells to chemotherapy. Moreover, we demonstrated that the E2F3 was a direct target of miR-125b in breast cancer cells.

Conclusions/Significance

These data suggest that circulating miR-125b expression is associated with chemotherapeutic resistance of breast cancer. This finding has important implications in the development of targeted therapeutics for overcoming chemotherapeutic resistance in novel anti-cancer strategies.     

Glucosamine suppresses proliferation of human prostate carcinoma DU145 cells through inhibition of STAT3 signaling

Background  

Glucosamine is known as a toxic agent for several malignant cell lines and transplanted tumors with little toxicity to normal host tissues. However, the mechanisms underlying anticancer activity of glucosamine are poorly understood. To study the mechanisms, the human prostate cancer DU145 cells were used for the model.     

Utilization of Neoadjuvant Chemotherapy Varies in the Treatment of Women with Invasive Breast Cancer

Background

Treatment with neoadjuvant chemotherapy (NAC) has made it possible for some women to be successfully treated with breast conservation therapy (BCT ) who were initially considered ineligible. Factors related to current practice patterns of NAC use are important to understand particularly as the surgical treatment of invasive breast cancer has changed. The goal of this study was to determine variations in neoadjuvant chemotherapy use in a large multi-center national database of patients with breast cancer.

Methods

We evaluated NAC use in patients with initially operable invasive breast cancer and potential impact on breast conservation rates. Records of 2871 women ages 18-years and older diagnosed with 2907 invasive breast cancers from January 2003 to December 2008 at four institutions across the United States were examined using the Breast Cancer Surgical Outcomes (BRCASO) database. Main outcome measures included NAC use and association with pre-operatively identified clinical factors, surgical approach (partial mastectomy [PM] or total mastectomy [TM]), and BCT failure (initial PM followed by subsequent TM).

Results

Overall, NAC utilization was 3.8%l. Factors associated with NAC use included younger age, pre-operatively known positive nodal status, and increasing clinical tumor size. NAC use and BCT failure rates increased with clinical tumor size, and there was significant variation in NAC use across institutions. Initial TM frequency approached initial PM frequency for tumors >30-40mm; BCT failure rate was 22.7% for tumors >40mm. Only 2.7% of patients undergoing initial PM and 7.2% undergoing initial TM received NAC.

Conclusions

NAC use in this study was infrequent and varied among institutions. Infrequent NAC use in patients suggests that NAC may be underutilized in eligible patients desiring breast conservation.     

肿瘤干细胞对恶性肿瘤辅助治疗的影响

放化疗是目前恶性肿瘤治疗的重要手段,但是迄今为止,除了手术以外,几乎没有能单独根治恶性肿瘤的治疗方法,甚至一些恶性肿瘤在手术、化疗或放疗后会出现再生和侵袭能力增强,被称为恶性肿瘤治疗后再增殖,这可能是恶性肿瘤治疗失败的主要原因,其主要机制可能是肿瘤干细胞(cancer stem cells,CSCs)对放化疗的耐受,以及放化疗导致肿瘤细胞的上皮细胞间质化,继而提高了肿瘤侵袭性。该文将从CSCs的角度重新探讨放化疗等辅助治疗对恶性肿瘤的影响。     

Ability of the Met Kinase Inhibitor Crizotinib and New Generation EGFR Inhibitors to Overcome Resistance to EGFR Inhibitors

Purpose

Although EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have shown dramatic effects against EGFR mutant lung cancer, patients ultimately develop resistance by multiple mechanisms. We therefore assessed the ability of combined treatment with the Met inhibitor crizotinib and new generation EGFR-TKIs to overcome resistance to first-generation EGFR-TKIs.

Experimental Design

Lung cancer cell lines made resistant to EGFR-TKIs by the gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression and mice with tumors induced by these cells were treated with crizotinib and a new generation EGFR-TKI.

Results

The new generation EGFR-TKI inhibited the growth of lung cancer cells containing the gatekeeper EGFR-T790M mutation, but did not inhibit the growth of cells with Met amplification or HGF overexpression. In contrast, combined therapy with crizotinib plus afatinib or WZ4002 was effective against all three types of cells, inhibiting EGFR and Met phosphorylation and their downstream molecules. Crizotinib combined with afatinib or WZ4002 potently inhibited the growth of mouse tumors induced by these lung cancer cell lines. However, the combination of high dose crizotinib and afatinib, but not WZ4002, triggered severe adverse events.

Conclusions

Our results suggest that the dual blockade of mutant EGFR and Met by crizotinib and a new generation EGFR-TKI may be promising for overcoming resistance to reversible EGFR-TKIs but careful assessment is warranted clinically.