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1.
Gastrointestinal pharmacology: practical tips for the esophagologist.
Scarpignato, C, Sloan, JA, Wang, DH, Hunt, RH
Annals of the New York Academy of Sciences. 2020;(1):90-107
Abstract
Gastroesophageal reflux disease (GERD) is primarily a motor disorder, and its pathogenesis is multifactorial. As a consequence, treatment should be able to address the underlying pathophysiology. Proton pump inhibitors (PPIs) are the mainstay of medical therapy for GERD, but these drugs only provide the control of symptoms and lesions without curing the disease. However, continuous acid suppression with PPIs is recommended for patients with Barrett's esophagus because of their potential chemopreventive effects. In addition to the antisecretory activity, these compounds display several pharmacological properties, often overlooked in clinical practice. PPIs can indeed affect gastric motility, exert a mucosal protective effect, and an antioxidant, anti-inflammatory, and antineoplastic activity, also protecting cancer cells from developing chemo- or radiotherapeutic resistance. Even in the third millennium, current pharmacologic approaches to address GERD are limited. Reflux inhibitors represent a promise unfulfilled, effective and safe prokinetics are lacking, and antidepressants, despite being effective in selected patients, give rise to adverse events in a large proportion of them. While waiting for new drug classes (like potassium-competitive acid blockers), reassessing old drugs (namely alginate-containing formulations), and paving the new avenue of esophageal mucosal protection are, at the present time, the only reliable alternatives to acid suppression.
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2.
Lineage plasticity in cancer: a shared pathway of therapeutic resistance.
Quintanal-Villalonga, Á, Chan, JM, Yu, HA, Pe'er, D, Sawyers, CL, Sen, T, Rudin, CM
Nature reviews. Clinical oncology. 2020;(6):360-371
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Abstract
Lineage plasticity, the ability of cells to transition from one committed developmental pathway to another, has been proposed as a source of intratumoural heterogeneity and of tumour adaptation to an adverse tumour microenvironment including exposure to targeted anticancer treatments. Tumour cell conversion into a different histological subtype has been associated with a loss of dependency on the original oncogenic driver, leading to therapeutic resistance. A well-known pathway of lineage plasticity in cancer - the histological transformation of adenocarcinomas to aggressive neuroendocrine derivatives - was initially described in lung cancers harbouring an EGFR mutation, and was subsequently reported in multiple other adenocarcinomas, including prostate cancer in the presence of antiandrogens. Squamous transformation is a subsequently identified and less well-characterized pathway of adenocarcinoma escape from suppressive anticancer therapy. The increased practice of tumour re-biopsy upon disease progression has increased the recognition of these mechanisms of resistance and has improved our understanding of the underlying biology. In this Review, we provide an overview of the impact of lineage plasticity on cancer progression and therapy resistance, with a focus on neuroendocrine transformation in lung and prostate tumours. We discuss the current understanding of the molecular drivers of this phenomenon, emerging management strategies and open questions in the field.
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New Insights in Gene Expression Alteration as Effect of Paclitaxel Drug Resistance in Triple Negative Breast Cancer Cells.
Jurj, A, Pop, LA, Zanoaga, O, Ciocan-Cârtiţă, CA, Cojocneanu, R, Moldovan, C, Raduly, L, Pop-Bica, C, Trif, M, Irimie, A, et al
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2020;(4):648-664
Abstract
BACKGROUND/AIMS: Triple negative breast cancer (TNBC) is a highly aggressive form of cancer which lacks targeted therapy options. Thus, TNBC patients have poor outcomes and a decreased survival rate than patients with other types of breast cancers. Due to the lack of surface receptors, TNBC needs a comprehensive investigation to provide more information regarding patient's therapy, as well as to understand the way how to counteract drug resistance mechanisms. Nowadays, chemotherapy remains an unsolved issue which rise a lot of questions in oncology field. METHODS In this article, we investigated the implication of paclitaxel in TNBC cell lines after a prolong administration, after 12, respectively 24 passages followed by evaluation of morphological alteration, mutational pattern by next generation sequencing and the altered gene expression pattern by microarray technology and validation by qRT-PCR of the resistance to therapy relevant genes. RESULTS Using functional assays, we showed that paclitaxel exhibits antiproliferative activity on Hs578T/Pax and MDA-MB-231/Pax demonstrating the activation of cell death mechanisms. Confocal microscopy revealed significant modifications which occur in the morphological structure with a disruption of the actin-filaments and also mitotic catastrophe. The presence of these nuclear alterations is due to some modifications at the cellular and molecular levels. Important alterations at the transcriptomic and genomic levels were observed from this a common drug resistance signature (IL-6, CXCL8, VEGFA, EGR1, PTGS2 and TRIB1) for both cell lines at 24 passages was discovered. Also, an important mutation (TP53) linked with drug response was identified. CONCLUSION These results might be used to furnish novel biomarkers in TNBC, as well as to find a strategy to counteract the resistance to therapy in order to increase survival rate and to enhance the prognosis of patients with TNBC.
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Potential cytotoxic and anti-metastatic effects of berberine on gynaecological cancers with drug-associated resistance.
Mortazavi, H, Nikfar, B, Esmaeili, SA, Rafieenia, F, Saburi, E, Chaichian, S, Heidari Gorji, MA, Momtazi-Borojeni, AA
European journal of medicinal chemistry. 2020;:111951
Abstract
Gynaecological disorders, such as cervical, ovarian, and endometrial cancers are the second most prevalent cancer types in women worldwide. Therapeutic approaches for gynaecological cancers involve chemotherapy, radiation, and surgery. However, lifespan is not improved, and novel medications are required. Among various phytochemicals, berberine, a well-known natural product, has been shown to be a promising cancer chemopreventive agent. Pharmacokinetics, safety, and efficacy of berberine have been investigated in the several experiments against numerous diseases. Here, we aimed to provide a literature review from available published investigations showing the anticancer effects of berberine and its various synthetic analogues against gynaecological disorders, including cervical, ovarian, and endometrial cancers. In conclusion, berberine has been found to efficiently inhibit viability, proliferation, and migration of cancer cells, mainly, via induction of apoptosis by both mitochondrial dependent and -independent pathways. Additionally, structural modification of berberine showed that berberine analogues can improve its antitumor effects against gynaecological cancers.
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Phase I expansion cohort to evaluate the combination of bevacizumab, sorafenib and low-dose cyclophosphamide in children and young adults with refractory or recurrent solid tumours.
Federico, SM, Caldwell, KJ, McCarville, MB, Daryani, VM, Stewart, CF, Mao, S, Wu, J, Davidoff, AM, Santana, VM, Furman, WL, et al
European journal of cancer (Oxford, England : 1990). 2020;:35-42
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BACKGROUND Angiogenesis is critical for tumour growth and metastasis. Dual inhibition of vascular endothelial growth factors and platelet-derived growth factor receptors suppresses angiogenesis. This expansion cohort of a phase I study targeted angiogenesis with sorafenib, bevacizumab and low-dose cyclophosphamide in children and young adults with recurrent solid tumours. METHODS An expansion cohort including patients with refractory or recurrent solid tumours was enrolled and received bevacizumab (15 mg/kg IV, day 1), sorafenib (90 mg/m2 po twice daily, days 1-21) and low-dose cyclophosphamide (50 mg/m2 po daily, days 1-21). Each course was 21 days. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v3.0, and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. Serial bevacizumab pharmacokinetic (PK) studies were performed during course 1. RESULTS Twenty-four patients (15 males; median age 14.5 yrs; range 1-22 yr) received a median of 6 courses (range 1-18). Twelve patients had a bone or soft tissue sarcoma. The most common grade III/IV non-haematologic toxicities were hypertension (N = 4), hand/foot rash (N = 3) and elevated lipase (N = 3). The most common grade III/IV haematologic toxicities were neutropenia (N = 7) and lymphopenia (N = 17). Three patients (2 synovial sarcoma, 1 rhabdoid tumour) achieved a partial response and 18 had stable disease. The progression-free survival at 3 and 6 months were 78.1% (95% confidence interval [CI] 60.6-95.6%) and 54% (95% CI 30.2-78.2%), respectively. Bevacizumab PKs in 15 patients was similar to published adult PK results. CONCLUSIONS Intravenous bevacizumab combined with oral sorafenib and low-dose cyclophosphamide was tolerated and demonstrated promising activity in a subset of childhood solid tumours.
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Broad-Spectrum Preclinical Antitumor Activity of Chrysin: Current Trends and Future Perspectives.
Moghadam, ER, Ang, HL, Asnaf, SE, Zabolian, A, Saleki, H, Yavari, M, Esmaeili, H, Zarrabi, A, Ashrafizadeh, M, Kumar, AP
Biomolecules. 2020;(10)
Abstract
Pharmacological profile of phytochemicals has attracted much attention to their use in disease therapy. Since cancer is a major problem for public health with high mortality and morbidity worldwide, experiments have focused on revealing the anti-tumor activity of natural products. Flavonoids comprise a large family of natural products with different categories. Chrysin is a hydroxylated flavonoid belonging to the flavone category. Chrysin has demonstrated great potential in treating different disorders, due to possessing biological and therapeutic activities, such as antioxidant, anti-inflammatory, hepatoprotective, neuroprotective, etc. Over recent years, the anti-tumor activity of chrysin has been investigated, and in the present review, we provide a mechanistic discussion of the inhibitory effect of chrysin on proliferation and invasion of different cancer cells. Molecular pathways, such as Notch1, microRNAs, signal transducer and activator of transcription 3 (STAT3), nuclear factor-kappaB (NF-κB), PI3K/Akt, MAPK, etc., as targets of chrysin are discussed. The efficiency of chrysin in promoting anti-tumor activity of chemotherapeutic agents and suppressing drug resistance is described. Moreover, poor bioavailability, as one of the drawbacks of chrysin, is improved using various nanocarriers, such as micelles, polymeric nanoparticles, etc. This updated review will provide a direction for further studies in evaluating the anti-tumor activity of chrysin.
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The Hedgehog signaling pathway promotes chemotherapy resistance via multidrug resistance protein 1 in ovarian cancer.
Zhang, H, Hu, L, Cheng, M, Wang, Q, Hu, X, Chen, Q
Oncology reports. 2020;(6):2610-2620
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Abstract
Various studies have revealed that the Hedgehog (Hh) signaling pathway promotes ovarian cancer invasion, migration and drug resistance. Previous studies by our group have identified a set of genes, including multidrug resistance gene 1 (MDR1), that are regulated by Hh signaling in ovarian cancer. However, the association between Hh signaling activation and MDR1 expression requires further validation. In the present study, reverse transcription‑quantitative PCR or western blot assays were used to evaluate the mRNA and protein expression levels of MDR1, Sonic Hh (Shh), glioma‑associated oncogene 2 (Gli2), Gli1 and γ‑phosphorylated H2A.X variant histone (γ‑H2AX). MTT and colony‑formation assays were performed to determine the effect of cisplatin (DDP) after inhibiting the Hh pathway in ovarian cancer cells. The results indicated that MDR1, Gli2 and Shh levels were much higher in SK‑OV‑3 cells with acquired DDP resistance than in native SK‑OV‑3 cells. ES‑2 cells with overexpression of Gli2 were capable of efficiently forming colonies in the presence of low DDP concentrations. By contrast, Gli2 knockdown in SK‑OV‑3 cells decreased the colony‑forming ability under the same concentration of DDP. As determined by MTT assays, knockdown of Gli2 or targeting of the Hh signaling pathway with either Gli‑antagonist 61 (GANT61) or cyclopamine, in combination with DDP treatment, diminished the viability of ES‑2 and SK‑OV‑3 cells, whereas Gli2 overexpression increased the viability of ES‑2 cells in the presence of DDP. Knockdown of Gli2 or targeting the Hh signaling pathway with GANT61 also increased γ‑H2AX levels but decreased the expression of MDR1 in the presence of DDP. MDR1 expression is regulated by the Hh signaling pathway and is likely a downstream transcription factor of Gli2. In conclusion, targeting the Hh signaling pathway increases the sensitivity of ovarian cancer to DDP. MDR1 is a target gene of the Hh signaling pathway and this pathway may affect chemoresistance of ovarian cancer to DDP via MDR1.
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Phase Ia Study of Anti-NaPi2b Antibody-Drug Conjugate Lifastuzumab Vedotin DNIB0600A in Patients with Non-Small Cell Lung Cancer and Platinum-Resistant Ovarian Cancer.
Gerber, DE, Infante, JR, Gordon, MS, Goldberg, SB, Martín, M, Felip, E, Martinez Garcia, M, Schiller, JH, Spigel, DR, Cordova, J, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020;(2):364-372
Abstract
PURPOSE This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody-drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). PATIENTS AND METHODS LIFA was administered to patients with non-small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). RESULTS Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). CONCLUSIONS LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.
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Metallothionein isoforms as double agents - Their roles in carcinogenesis, cancer progression and chemoresistance.
Merlos Rodrigo, MA, Jimenez Jimemez, AM, Haddad, Y, Bodoor, K, Adam, P, Krizkova, S, Heger, Z, Adam, V
Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 2020;:100691
Abstract
Metallothioneins (MTs) are small cysteine-rich intracellular proteins with four major isoforms identified in mammals, designated MT-1 through MT-4. The best known biological functions of MTs are their ability to bind and sequester metal ions as well as their active role in redox homeostasis. Despite these protective roles, numerous studies have demonstrated that changes in MT expression could be associated with the process of carcinogenesis and participation in cell differentiation, proliferation, migration, and angiogenesis. Hence, MTs have the role of double agents, i.e., working with and against cancer. In view of their rich biochemical properties, it is not surprising that MTs participate in the emergence of chemoresistance in tumor cells. Many studies have demonstrated that MT overexpression is involved in the acquisition of resistance to anticancer drugs including cisplatin, anthracyclines, tyrosine kinase inhibitors and mitomycin. The evidence is gradually increasing for a cellular switch in MT functions, showing that they indeed have two faces: protector and saboteur. Initially, MTs display anti-oncogenic and protective roles; however, once the oncogenic process was launched, MTs are utilized by cancer cells for progression, survival, and contribution to chemoresistance. The duality of MTs can serve as a potential prognostic/diagnostic biomarker and can therefore pave the way towards the development of new cancer treatment strategies. Herein, we review and discuss MTs as tumor disease markers and describe their role in chemoresistance to distinct anticancer drugs.
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Phase II trial of eribulin in patients who do not achieve pathologic complete response (pCR) following neoadjuvant chemotherapy.
Yardley, DA, Peacock, N, Daniel, B, Anz, B, Molthrop, DC, Shroff, SK, Young, R, Jankov, A, Vander Woude, A, Shastry, M, et al
Breast cancer research and treatment. 2020;(3):647-655
Abstract
PURPOSE Women with residual invasive breast cancer at the primary site or axillary lymph nodes following neoadjuvant chemotherapy have a high risk of recurrence. Eribulin improves survival in patients with metastatic breast cancer who progress after anthracycline and taxane therapy. This phase 2 trial assessed the efficacy of postoperative eribulin in breast cancer patients who did not achieve a pCR following standard neoadjuvant chemotherapy. METHODS Women with localized breast cancer who had residual invasive cancer following ≥ 4 cycles of standard anthracycline and/or taxane-containing neoadjuvant chemotherapy received adjuvant eribulin treatment. HER2-positive patients also received trastuzumab for 1 year. Adjuvant hormonal therapy and locoregional radiotherapy were administered as per institutional guidelines. Primary endpoint was the 2-year DFS rate. Three patient cohorts were analyzed: TNBC (Cohort A), HR+/HER2- (Cohort B), and HER2+ (Cohort C). RESULTS One hundred twenty-six patients (Cohort A-53, Cohort B-42, and Cohort C-31) were enrolled. Neoadjuvant chemotherapy included a taxane and an anthracycline in 70%. Eribulin was well tolerated; 84% of patients received the planned 6 cycles. After a median follow-up of 28 months, the 24-month DFS rates were 56% (95% CI 42, 69), 83% (95% CI 67, 91), and 73% (95% CI 53, 86) for Cohorts A, B, and C, respectively. The most common grade 3/4 treatment-related adverse events were neutropenia (26%), leukopenia (13%), and neuropathy (7%). CONCLUSION Administration of adjuvant eribulin after neoadjuvant chemotherapy was feasible and well tolerated. The 24-month DFS rate did not reach the study target levels in any of the cohorts and was similar to DFS previously described in these cohorts following neoadjuvant chemotherapy alone.