Topical Collection "Drug Resistance and Novel Therapies in Cancers"

Editor

Collection Editor
Prof. Zhixiang Wang

Signal Transduction Research Group, Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
Website | E-Mail
Phone: +1-780-492-0710
Fax: +1-780-492-1998
Interests: ErbB receptors; cell signaling; protein trafficking; breast cancer; small GTPases and cell cycle

Topical Collection Information

Dear Colleagues,

Cancer is among the leading causes of mortality in developed countries. Despite advances in treatment in all settings, disease recurrence and progression remains a major obstacle to therapy. One of the main clinical issues is the development of drug resistance. Drug resistance exists in two forms: Acquired resistance, where the drug is initially efficient but becomes ineffective over time, while intrinsic resistance occurs when a drug is ineffective from the beginning of treatment. The hallmarks of drug resistance in cancers include sustained tumor cell proliferation, insensitive to growth suppressors, resisting cell death, and active invasion.

The early drugs used in cancer treatment are all of chemical origin, and as thus, drug resistance is also called chemoresistance in cancer. However, with the development of novel cancer treatment agents, such as hormones, cytokines, antibodies, antisense oligonucleotides and siRNAs, cancer drugs now could include any agent that is used to treat cancer patients. Therefore the term drug resistance in cancer could be used to cover resistance to any cancer treatment agents.

Through intensive studies, multiple mechanisms have been identified for the development of drug resistance. In general, drug resistance could arise due to decreased intracellular drug concentrations, alterations of drug targets, epigenetic modification, and activation of certain signaling cascades These mechanisms include drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, the epithelial-mesenchymal transition (EMT), and epigenetic modifications.

Many strategies have been developed to combat drug resistance, either by combining the currently available therapies or by developing novel therapies. While new chemotherapeutic agents are still developed and chemotherapy is still standard-of-care in the treatment of most cancers, the focus has shift to the development and application of novel therapeutic agents for immunotherapy and targeted therapy due to the improved understanding of tumor biology and the hallmarks of cancers. Targeted therapies have frequently been used in combination with chemotherapeutic agents and radiotherapy in some cases.

Prof. Dr. Zhixiang Wang
Collection Editor

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Keywords

  • cancer
  • chemotherapy
  • novel therapy
  • drug resistance
  • multidrug resistance
  • intrinsic drug resistance
  • acquired drug resistance
  • metastasis
  • apoptosis
  • disease recurrence
  • targeted therapy
  • immunotherapy
  • hormones
  • cytokines
  • antibodies
  • antisense oligonucleotides
  • siRNAs

Published Papers (14 papers)

2019

Jump to: 2018

Open AccessArticle Long-Term Outcomes of Carbon-Ion Radiotherapy for Malignant Gynecological Melanoma
Cancers 2019, 11(4), 482; https://doi.org/10.3390/cancers11040482
Received: 18 March 2019 / Revised: 1 April 2019 / Accepted: 2 April 2019 / Published: 4 April 2019
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Abstract
Surgical resection is considered a standard therapy for malignant melanoma (MM). However, it has not yet been established as an optimal treatment strategy for gynecological MMs, particularly owing to their very low incidence rates. We retrospectively analyzed clinical outcomes of carbon-ion radiotherapy (C-ion [...] Read more.
Surgical resection is considered a standard therapy for malignant melanoma (MM). However, it has not yet been established as an optimal treatment strategy for gynecological MMs, particularly owing to their very low incidence rates. We retrospectively analyzed clinical outcomes of carbon-ion radiotherapy (C-ion RT) for gynecological MMs. The eligibility criterion was the presence of histologically confirmed gynecological MM. Patients with pelvic or inguinal lymph node metastases were included, while those with distant metastases were excluded. The pelvic and inguinal lymph node regions were irradiated with up to 36 gray relative biological effectiveness (Gy (RBE)) followed by a gross tumor volume boost of up to 57.6 Gy (RBE) or 64 Gy (RBE) in 16 fractions over 4 weeks. Thirty-seven patients (median age: 71 years) were examined. In total, 22 patients had vaginal tumors, 12 had vulval tumors, and 3 had cervical uterine tumors. The median follow-up periods were 23 months (range: 5–103 months) for all patients and 53 months (range: 16–103 months) for survivors. Thirty of 37 patients (81%) achieved complete tumor disappearance. The 2-year local control, overall survival, and progression-free survival rates were 71%, 53%, and 29%, respectively. C-ion RT may be a definitive treatment option for patients with gynecological MM. Full article
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Open AccessArticle Increase Paclitaxel Sensitivity to Better Suppress Serous Epithelial Ovarian Cancer via Ablating Androgen Receptor/Aryl Hydrocarbon Receptor-ABCG2 Axis
Cancers 2019, 11(4), 463; https://doi.org/10.3390/cancers11040463
Received: 9 January 2019 / Revised: 11 March 2019 / Accepted: 27 March 2019 / Published: 2 April 2019
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Abstract
Background: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies and presents chemoresistance after chemotherapy treatment. Androgen receptor (AR) has been known to participate in proliferation. Yet the mechanisms of the resistance of this drug and its linkage to the [...] Read more.
Background: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies and presents chemoresistance after chemotherapy treatment. Androgen receptor (AR) has been known to participate in proliferation. Yet the mechanisms of the resistance of this drug and its linkage to the AR remains unclear. Methods: To elucidate AR-related paclitaxel sensitivity, co-IP, luciferase reporter assay and ChIP assay were performed to identify that AR direct-regulated ABCG2 expression under paclitaxel treatment. IHC staining by AR antibody presented higher AR expression in serous-type patients than other types. AR degradation enhancer (ASC-J9) was used to examine paclitaxel-associated and paclitaxel-resistant cytotoxicity in vitro and in vivo. Results: We found AR/aryl hydrocarbon receptor (AhR)-mediates ABCG2 expression and leads to a change in paclitaxel cytotoxicity/sensitivity in EOC serous subtype cell lines. Molecular mechanism study showed that paclitaxel activated AR transactivity and bound to alternative ARE in the ABCG2 proximal promoter region. To identify AR as a potential therapeutic target, the ASC-J9 was used to re-sensitize paclitaxel-resistant EOC tumors upon paclitaxel treatment in vitro and in vivo. Conclusion: The results demonstrated that activation of AR transactivity beyond the androgen-associated biological effect. This novel AR mechanism explains that degradation of AR is the most effective therapeutic strategy for treating AR-positive EOC serous subtype. Full article
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Open AccessArticle The Effects of Pertuzumab and Its Combination with Trastuzumab on HER2 Homodimerization and Phosphorylation
Cancers 2019, 11(3), 375; https://doi.org/10.3390/cancers11030375
Received: 8 February 2019 / Revised: 11 March 2019 / Accepted: 12 March 2019 / Published: 16 March 2019
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Abstract
Pertuzumab (Perjeta) is an anti-HER2 monoclonal antibody that is used for treatment of HER2-positive breast cancers in combination with trastuzumab (Herceptin) and docetaxel and showed promising clinical outcomes. Pertuzumab is suggested to block heterodimerization of HER2 with EGFR and HER3 that abolishes canonical [...] Read more.
Pertuzumab (Perjeta) is an anti-HER2 monoclonal antibody that is used for treatment of HER2-positive breast cancers in combination with trastuzumab (Herceptin) and docetaxel and showed promising clinical outcomes. Pertuzumab is suggested to block heterodimerization of HER2 with EGFR and HER3 that abolishes canonical function of HER2. However, evidence on the exact mode of action of pertuzumab in homodimerization of HER2 are limited. In this study, we investigated the effect of pertuzumab and its combination with trastuzumab on HER2 homodimerization, phosphorylation and whole gene expression profile in Chinese hamster ovary (CHO) cells stably overexpressing human HER2 (CHO-K6). CHO-K6 cells were treated with pertuzumab, trastuzumab, and their combination, and then HER2 homodimerization and phosphorylation at seven pY sites were investigated. The effects of the monoclonal antibodies on whole gene expression and the expression of cell cycle stages, apoptosis, autophagy, and necrosis were studied by cDNA microarray. Results showed that pertuzumab had no significant effect on HER2 homodimerization, however, trastuzumab increased HER2 homodimerization. Interestingly, pertuzumab increased HER2 phosphorylation at Y1127, Y1139, and Y1196 residues, while trastuzumab increased HER2 phosphorylation at Y1196. More surprisingly, combination of pertuzumab and trastuzumab blocked the phosphorylation of Y1005 and Y1127 of HER2. Our results also showed that pertuzumab, but not trastuzumab, abrogated the effect of HER2 overexpression on cell cycle in particular G1/S transition, G2/M transition, and M phase, whereas trastuzumab abolished the inhibitory effect of HER2 on apoptosis. Our findings confirm that pertuzumab is unable to inhibit HER2 homodimerization but induces HER2 phosphorylation at some pY sites that abolishes HER2 effects on cell cycle progress. These data suggest that the clinical effects of pertuzumab may mostly through the inhibition of HER2 heterodimers, rather than HER2 homodimers and that pertuzumab binding to HER2 may inhibit non-canonical HER2 activation and function in non-HER-mediated and dimerization-independent pathway(s). Full article
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Open AccessArticle Cucurbitacin D Reprograms Glucose Metabolic Network in Prostate Cancer
Cancers 2019, 11(3), 364; https://doi.org/10.3390/cancers11030364
Received: 30 October 2018 / Revised: 25 February 2019 / Accepted: 8 March 2019 / Published: 14 March 2019
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Abstract
Prostate cancer (PrCa) metastasis is the major cause of mortality and morbidity among men. Metastatic PrCa cells are typically adopted for aberrant glucose metabolism. Thus, chemophores that reprogram altered glucose metabolic machinery in cancer cells can be useful agent for the repression of [...] Read more.
Prostate cancer (PrCa) metastasis is the major cause of mortality and morbidity among men. Metastatic PrCa cells are typically adopted for aberrant glucose metabolism. Thus, chemophores that reprogram altered glucose metabolic machinery in cancer cells can be useful agent for the repression of PrCa metastasis. Herein, we report that cucurbitacin D (Cuc D) effectively inhibits glucose uptake and lactate production in metastatic PrCa cells via modulating glucose metabolism. This metabolic shift by Cuc D was correlated with decreased expression of GLUT1 by its direct binding as suggested by its proficient molecular docking (binding energy −8.5 kcal/mol). Cuc D treatment also altered the expression of key oncogenic proteins and miR-132 that are known to be involved in glucose metabolism. Cuc D (0.1 to 1 µM) treatment inhibited tumorigenic and metastatic potential of human PrCa cells via inducing apoptosis and cell cycle arrest in G2/M phase. Cuc D treatment also showed inhibition of tumor growth in PrCa xenograft mouse model with concomitant decrease in the expression of GLUT1, PCNA and restoration of miR-132. These results suggest that Cuc D is a novel modulator of glucose metabolism and could be a promising therapeutic modality for the attenuation of PrCa metastasis. Full article
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Open AccessCorrection Correction: Hiroshi Sugano et al. Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells. Cancers 2018, 10, 386
Cancers 2019, 11(3), 335; https://doi.org/10.3390/cancers11030335
Received: 6 March 2019 / Accepted: 6 March 2019 / Published: 8 March 2019
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Abstract
The authors would like to make a correction to their published paper [...] Full article
Open AccessArticle Expression of Neural Crest Markers GLDC and ERRFI1 is Correlated with Melanoma Prognosis
Received: 21 November 2018 / Revised: 14 December 2018 / Accepted: 14 December 2018 / Published: 11 January 2019
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Abstract
Regulation of particular genes during the formation of neural crest (NC) cells is also described during progression of malignant melanoma. In this context, it is of paramount importance to develop neural crest models allowing the identification of candidate genes, which could be used [...] Read more.
Regulation of particular genes during the formation of neural crest (NC) cells is also described during progression of malignant melanoma. In this context, it is of paramount importance to develop neural crest models allowing the identification of candidate genes, which could be used as biomarkers for melanoma prognosis. Here, we used a human induced Pluripotent Stem Cells (iPSC)-based approach to present novel NC-associated genes, expression of which was upregulated in melanoma. A list of 8 candidate genes, based on highest upregulation, was tested for prognostic value in a tissue microarray analysis containing samples from advanced melanoma (good versus bad prognosis) as well as from high-risk primary melanomas (early metastasizing versus non or late-metastasizing). CD271, GLDC, and ERRFI1 showed significantly higher expression in metastatic patients who died early than the ones who survived at least 30 months. In addition, GLDC and TWIST showed a significantly higher immunohistochemistry (IHC) score in primary melanomas from patients who developed metastases within 12 months versus those who did not develop metastases in 30 months. In conclusion, our iPSC-based study reveals a significant association of NC marker GLDC protein expression with melanoma prognosis. Full article
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2018

Jump to: 2019

Open AccessArticle Interplay between Epigenetics, Expression of Estrogen Receptor- α, HER2/ERBB2 and Sensitivity of Triple Negative Breast Cancer Cells to Hormonal Therapy
Received: 17 October 2018 / Revised: 12 December 2018 / Accepted: 19 December 2018 / Published: 21 December 2018
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Abstract
Triple negative breast cancer (TNBC) cells are resistant to hormonal/targeted therapies. This study aims to investigate epigenetic differences between TNBC and other types of breast cancer and the effect of epigenetic modulation on the response of TNBC cells to hormonal therapy. Thus, we [...] Read more.
Triple negative breast cancer (TNBC) cells are resistant to hormonal/targeted therapies. This study aims to investigate epigenetic differences between TNBC and other types of breast cancer and the effect of epigenetic modulation on the response of TNBC cells to hormonal therapy. Thus, we investigated (i) the expression of different epigenetic markers, (ii) the effect of epigenetic modifying agents on the expression of ERα and HER2/ERBB2 and (iii) the effect on the response to tamoxifen in four breast cancer cell lines with different hormonal receptor status. Our results revealed a differential expression patterns of epigenetic markers in the four breast cancer cells. In TNBC cells, histone deacetylases (HDAC) 1 and 2 were less expressed, whereas HDACs 4 and 6 were overexpressed. Interestingly, treatment with epigenetic modifiers resulted in (i) a pronounced increase in the expression of ERα and HER2/ERBB2 along with (ii) an increase in the sensitivity of TNBC cells to tamoxifen. Collectively, this study indicates a different epigenetic background for TNBC cells, which represses the expression of ERα and HER2/ERBB2. Furthermore, we provide here the rationale for the use of epigenetic modifiers to enhance the response of TNBC to hormonal therapy through upregulation of ERα. Full article
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Open AccessArticle ATM Dependent DUSP6 Modulation of p53 Involved in Synergistic Targeting of MAPK and p53 Pathways with Trametinib and MDM2 Inhibitors in Cutaneous Melanoma
Received: 21 November 2018 / Revised: 17 December 2018 / Accepted: 18 December 2018 / Published: 20 December 2018
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Abstract
MAPK and p14ARF–MDM2–p53 pathways are critical in cutaneous melanomas. Here, synergistic combination of the MEK inhibitor, trametinib, with MDM2 inhibitors, nutlin-3/RG7388/HDM201, and the mechanistic basis of responses, for BRAFV600E and p53WT melanoma cells, are reported. The combination treatments induced [...] Read more.
MAPK and p14ARF–MDM2–p53 pathways are critical in cutaneous melanomas. Here, synergistic combination of the MEK inhibitor, trametinib, with MDM2 inhibitors, nutlin-3/RG7388/HDM201, and the mechanistic basis of responses, for BRAFV600E and p53WT melanoma cells, are reported. The combination treatments induced higher levels of p53 target gene transcripts and protein products, resulting in increased cell cycle arrest and apoptosis compared with MDM2 inhibitors alone, suggesting trametinib synergized with MDM2 inhibitors via upregulation of p53-dependent pathways. In addition, DUSP6 phosphatase involvement was indicated by downregulation of its mRNA and protein following pERK reduction by trametinib. Furthermore, suppression of DUSP6 by siRNA, or inhibition with the small molecule inhibitor, BCI, at a dose without cytotoxicity, potentiated the effect of MDM2 inhibitors through increased ATM-dependent p53 phosphorylation, as demonstrated by complete reversal with the ATM inhibitor, KU55933. Trametinib synergizes with MDM2 inhibitors through a novel DUSP6 mechanism in BRAFV600E and p53WT melanoma cells, in which DUSP6 regulation of p53 phosphorylation is mediated by ATM. This provides a new therapeutic rationale for combination treatments involving activation of the ATM/p53 pathway and MAPK pathway inhibition. Full article
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Open AccessArticle Targeted Therapy-Resistant Melanoma Cells Acquire Transcriptomic Similarities with Human Melanoblasts
Cancers 2018, 10(11), 451; https://doi.org/10.3390/cancers10110451
Received: 11 October 2018 / Revised: 6 November 2018 / Accepted: 13 November 2018 / Published: 16 November 2018
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Abstract
The mechanisms of adaptive and acquired drug resistance in tumors are not completely understood. So far, gene amplifications or mutations, leading to the reactivation of the MAPK or PI3K pathways have been described. In this study, we used two different methods to generate [...] Read more.
The mechanisms of adaptive and acquired drug resistance in tumors are not completely understood. So far, gene amplifications or mutations, leading to the reactivation of the MAPK or PI3K pathways have been described. In this study, we used two different methods to generate human melanoblasts: (1) via differentiation from induced pluripotent stem cells (iPSCs) and (2) via dedifferentiation from melanocytes. The melanoblast transcriptomes were then compared to the transcriptome of MAPK inhibitor-resistant melanoma cells. We observed that the expression of genes associated with cell cycle control, DNA damage control, metabolism, and cancer was altered in both melanoblast populations and in both adaptive and acquired resistant melanoma samples, compared to drug-sensitive samples. However, genes involved in antigen presentation and cellular movement were only regulated in the melanoblast populations and in the acquired resistant melanoma samples, compared to the drug-sensitive samples. Moreover, melanocyte-derived melanoblasts and adaptive resistant melanoma samples were characterized by different expression levels of certain transcription factors or genes involved in the CDK5 pathway. In conclusion, we show here that in vitro models of human melanoblasts are very important tools to comprehend the expression profiles of drug-resistant melanoma. Full article
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Open AccessReview NF-κB Signaling in Targeting Tumor Cells by Oncolytic Viruses—Therapeutic Perspectives
Cancers 2018, 10(11), 426; https://doi.org/10.3390/cancers10110426
Received: 4 October 2018 / Revised: 4 November 2018 / Accepted: 6 November 2018 / Published: 8 November 2018
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Abstract
In recent years, oncolytic virotherapy became a promising therapeutic approach, leading to the introduction of a novel generation of anticancer drugs. However, despite evoking an antitumor response, introducing an oncolytic virus (OV) to the patient is still inefficient to overcome both tumor protective [...] Read more.
In recent years, oncolytic virotherapy became a promising therapeutic approach, leading to the introduction of a novel generation of anticancer drugs. However, despite evoking an antitumor response, introducing an oncolytic virus (OV) to the patient is still inefficient to overcome both tumor protective mechanisms and the limitation of viral replication by the host. In cancer treatment, nuclear factor (NF)-κB has been extensively studied among important therapeutic targets. The pleiotropic nature of NF-κB transcription factor includes its involvement in immunity and tumorigenesis. Therefore, in many types of cancer, aberrant activation of NF-κB can be observed. At the same time, the activity of NF-κB can be modified by OVs, which trigger an immune response and modulate NF-κB signaling. Due to the limitation of a monotherapy exploiting OVs only, the antitumor effect can be enhanced by combining OV with NF-κB-modulating drugs. This review describes the influence of OVs on NF-κB activation in tumor cells showing NF-κB signaling as an important aspect, which should be taken into consideration when targeting tumor cells by OVs. Full article
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Open AccessReview Systemic Therapy for Hepatocellular Carcinoma: Latest Advances
Cancers 2018, 10(11), 412; https://doi.org/10.3390/cancers10110412
Received: 2 October 2018 / Revised: 23 October 2018 / Accepted: 25 October 2018 / Published: 30 October 2018
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Abstract
Systemic therapy for hepatocellular carcinoma (HCC) has changed drastically since the introduction of the molecular targeted agent sorafenib in 2007. Although sorafenib expanded the treatment options for extrahepatic spread (EHS) and vascular invasion, making long-term survival of patients with advanced disease achievable to [...] Read more.
Systemic therapy for hepatocellular carcinoma (HCC) has changed drastically since the introduction of the molecular targeted agent sorafenib in 2007. Although sorafenib expanded the treatment options for extrahepatic spread (EHS) and vascular invasion, making long-term survival of patients with advanced disease achievable to a certain extent, new molecular-targeted agents are being developed as alternatives to sorafenib due to shortcomings such as its low response rate and high toxicity. Every single one of the many drugs developed during the 10-year period from 2007 to 2016 was a failure. However, during the two-year period from 2017 through 2018, four drugs—regorafenib, lenvatinib, cabozantinib, and ramucirumab—emerged successfully from clinical trials in quick succession and became available for clinical use. The efficacy of combination therapy with transcatheter arterial chemoembolization (TACE) plus sorafenib was also first demonstrated in 2018. Recently, immune checkpoint inhibitors have been applied to HCC treatment and many phase III clinical trials are ongoing, not only on monotherapy with nivolumab, pembrolizumab, and tislelizumab, but also on combination therapy with checkpoint inhibitors, programmed death-1 (PD-1) or PD-ligand 1 (PD-L1) antibody plus a molecular targeted agent (bevacizumab) or the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, tremelimumab. These combination therapies have shown higher response rates than PD-1/PD-L1 monotherapy alone, suggesting a synergistic effect by combination therapy in early phases; therefore, further results are eagerly awaited. Full article
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Open AccessArticle Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells
Cancers 2018, 10(10), 386; https://doi.org/10.3390/cancers10100386
Received: 19 September 2018 / Revised: 12 October 2018 / Accepted: 15 October 2018 / Published: 17 October 2018
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Abstract
Neoadjuvant chemoradiotherapy followed by radical surgery is the standard treatment for patients with locally advanced low rectal cancer. However, several studies have reported that ionizing radiation (IR) activates nuclear factor kappa B (NF-κB) that causes radioresistance and induces matrix metalloproteinase (MMP)-2/-9, which promote [...] Read more.
Neoadjuvant chemoradiotherapy followed by radical surgery is the standard treatment for patients with locally advanced low rectal cancer. However, several studies have reported that ionizing radiation (IR) activates nuclear factor kappa B (NF-κB) that causes radioresistance and induces matrix metalloproteinase (MMP)-2/-9, which promote tumor migration and invasion. Nafamostat mesilate (FUT175), a synthetic serine protease inhibitor, enhances the chemosensitivity to cytotoxic agents in digestive system cancer cells by inhibiting NF-κB activation. Therefore, we evaluated the combined effect of IR and FUT175 on cell proliferation, migration and invasion of colorectal cancer (CRC) cells. IR-induced upregulation of intranuclear NF-κB, FUT175 counteracted this effect. Moreover, the combination treatment suppressed cell viability and induced apoptosis. Similar effects were also observed in xenograft tumors. In addition, FUT175 prevented the migration and invasion of cancer cells caused by IR by downregulating the enzymatic activity of MMP-2/-9. In conclusion, FUT175 enhances the anti-tumor effect of radiotherapy through downregulation of NF-κB and reduces IR-induced tumor invasiveness by directly inhibiting MMP-2/-9 in CRC cells. Therefore, the use of FUT175 during radiotherapy might improve the efficacy of radiotherapy in patients with CRC. Full article
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Open AccessArticle Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment
Cancers 2018, 10(10), 375; https://doi.org/10.3390/cancers10100375
Received: 21 August 2018 / Revised: 25 September 2018 / Accepted: 3 October 2018 / Published: 10 October 2018
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Abstract
To find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and mefloquine synergize to selectively evoke a cytotoxic response in TSC2-deficient [...] Read more.
To find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and mefloquine synergize to selectively evoke a cytotoxic response in TSC2-deficient cell lines with mTORC1 hyperactivity. We optimize the concentrations of nelfinavir and mefloquine to a clinically viable range that kill cells that lack TSC2, while wild-type cells tolerate treatment. This new clinically viable drug combination causes a significant level of cell death in TSC2-deficient tumor spheroids. Furthermore, no cell recovery was apparent after drug withdrawal, revealing potent cytotoxicity. Transcriptional profiling by RNA sequencing of drug treated TSC2-deficient cells compared to wild-type cells suggested the cytotoxic mechanism of action, involving initial ER stress and an imbalance in energy homeostatic pathways. Further characterization revealed that supplementation with methyl pyruvate alleviated energy stress and reduced the cytotoxic effect, implicating energy deprivation as the trigger of cell death. This work underpins a critical vulnerability with cancer cells with aberrant signaling through the TSC2-mTORC1 pathway that lack flexibility in homeostatic pathways, which could be exploited with combined nelfinavir and mefloquine treatment. Full article
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Open AccessReview Mechanisms Underlying the Action and Synergism of Trastuzumab and Pertuzumab in Targeting HER2-Positive Breast Cancer
Cancers 2018, 10(10), 342; https://doi.org/10.3390/cancers10100342
Received: 8 August 2018 / Revised: 13 September 2018 / Accepted: 18 September 2018 / Published: 20 September 2018
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Abstract
Human epidermal growth factor receptor (HER) 2 (HER2) is overexpressed in 20–30% of breast cancers. HER2 is a preferred target for treating HER2-positive breast cancer. Trastuzumab and pertuzumab are two HER2-targeted monoclonal antibodies approved by the Food and Drug Administration (FDA) to use [...] Read more.
Human epidermal growth factor receptor (HER) 2 (HER2) is overexpressed in 20–30% of breast cancers. HER2 is a preferred target for treating HER2-positive breast cancer. Trastuzumab and pertuzumab are two HER2-targeted monoclonal antibodies approved by the Food and Drug Administration (FDA) to use as adjuvant therapy in combination with docetaxel to treat metastatic HER2-positive breast cancer. Adding the monoclonal antibodies to treatment regimen has changed the paradigm for treatment of HER2-positive breast cancer. Despite improving outcomes, the percentage of the patients who benefit from the treatment is still low. Continued research and development of novel agents and strategies of drug combinations is needed. A thorough understanding of the molecular mechanisms underlying the action and synergism of trastuzumab and pertuzumab is essential for moving forward to achieve high efficacy in treating HER2-positive breast cancer. This review examined and analyzed findings and hypotheses regarding the action and synergism of trastuzumab and pertuzumab and proposed a model of synergism based on available information. Full article
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