A phase 2 study of the combination of gemcitabine and cisplatin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines with/ without taxanes

Kohail, H.; Shehata, Samir; Mansour, Omar; Gouda, Y.; Gaafar, Rabbab; Hamid, Thoraya Abdel; Nowieam, Saiid El; Khodary, Ahmed Al; Zawahry, H. El; Wareth, A. A.; Halim, I. Abdel; Taleb, Fouad Abou; Hamada, Emad; Barsoum, Mohsen Samy; Abdullah, Mohamed; Meshref, Mohamed

doi:10.5144/1658-3876.2012.42

Cited by 7 publications

(6 citation statements)

References 11 publications

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“…It is used in combination with other drugs for the treatment of locally advanced or metastatic non-small-cell lung cancer, bladder cancer, and ovarian cancer, and as a single agent for the treatment of adenocarcinoma of the pancreas 4. Clinical studies have also demonstrated its extensive activity against breast carcinomas, including male breast cancer,5 metastatic breast cancer, and triple-negative breast cancer 6,7. In recent years, gemcitabine resistance has emerged and has become a serious concern in clinical practice; however, the exact mechanism of gemcitabine resistance in breast cancer is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways

Yang¹,

Lin²,

Guo³

et al. 2014

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Chemoresistance is a major cause of cancer treatment failure and leads to a reduction in the survival rate of cancer patients. Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and mitogen-activated protein kinase (MAPK) pathways are aberrantly activated in many malignant tumors, including breast cancer, which may indicate an association with breast cancer chemoresistance. In this study, we generated a chemoresistant human breast cancer cell line, MDA-MB-231/gemcitabine (simplified hereafter as “231/Gem”), from MDA-MB-231 human breast cancer cells. Flow cytometry studies revealed that with the same treatment concentration of gemcitabine, 231/Gem cells displayed more robust resistance to gemcitabine, which was reflected by fewer apoptotic cells and enhanced percentage of S-phase cells. Through the use of inverted microscopy, Cell Counting Kit-8, and Transwell assays, we found that compared with parental 231 cells, 231/Gem cells displayed more morphologic projections, enhanced cell proliferative ability, and improved cell migration and invasion. Mechanistic studies revealed that the PI3K/AKT/mTOR and mitogen-activated protein kinase kinase (MEK)/MAPK signaling pathways were activated through elevated expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-AKT, mTOR, p-mTOR, p-P70S6K, and reduced expression of p-P38 and LC3-II (the marker of autophagy) in 231/Gem in comparison to control cells. However, there was no change in the expression of Cyclin D1 and p-adenosine monophosphate-activated protein kinase (AMPK). In culture, inhibitors of PI3K/AKT and mTOR, but not of MEK/MAPK, could reverse the enhanced proliferative ability of 231/Gem cells. Western blot analysis showed that treatment with a PI3K/AKT inhibitor decreased the expression levels of p-AKT, p-MEK, p-mTOR, and p-P70S6K; however, treatments with either MEK/MAPK or mTOR inhibitor significantly increased p-AKT expression. Thus, our data suggest that gemcitabine resistance in breast cancer cells is mainly mediated by activation of the PI3K/AKT signaling pathway. This occurs through elevated expression of p-AKT protein to promote cell proliferation and is negatively regulated by the MEK/MAPK and mTOR pathways.

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Section: Introductionmentioning

confidence: 99%

Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways

Yang¹,

Lin²,

Guo³

et al. 2014

OTT

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“…Although effective, most combinations have adverse side effects, including neutropenia, neuropathy, and cardiotoxicity, and many tumors still progress to metastasis 4 , 9 . Regimes with a more tolerable toxicity tend to yield a much lower overall response rate 10 , 11 . There is, therefore, a great need to improve efficacy of existing combination therapies by mitigating toxic side effects and improving complete response rates.…”

Section: Introductionmentioning

confidence: 99%

High-throughput screen identifies disulfiram as a potential therapeutic for triple-negative breast cancer cells: Interaction with IQ motif-containing factors

et al. 2013

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Triple-negative breast cancer (TNBC) represents an aggressive subtype, for which radiation and chemotherapy are the only options. Here we describe the identification of disulfiram, an FDA-approved drug used to treat alcoholism, as well as the related compound thiram, as the most potent growth inhibitors following high-throughput screens of 3185 compounds against multiple TNBC cell lines. The average IC50 for disulfiram was ~300 nM. Drug affinity responsive target stability (DARTS) analysis identified IQ motif-containing factors IQGAP1 and MYH9 as direct binding targets of disulfiram. Indeed, knockdown of these factors reduced, though did not completely abolish, cell growth. Combination treatment with 4 different drugs commonly used to treat TNBC revealed that disulfiram synergizes most effectively with doxorubicin to inhibit cell growth of TNBC cells. Disulfiram and doxorubicin cooperated to induce cell death as well as cellular senescence, and targeted the ESA+/CD24-/low/CD44+ cancer stem cell population. Our results suggest that disulfiram may be repurposed to treat TNBC in combination with doxorubicin.

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“…A study from Egypt reported on gemcitabine and cisplatin in locally advanced or metastatic BC after previous anthracycline therapy. In 132 patients, there was a 33% response rate and a 46% rate of stable disease was seen [38]. A study from Egypt compared anthracycline-based chemotherapy with or without docetaxel in estrogen receptor-positive pT1-2 BC (n = 60).…”

Section: Surgery and Adjuvant Treatment Of Bcmentioning

confidence: 99%

A Review on Breast Cancer Care in Africa

et al. 2015

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Background: The global incidence of breast cancer (BC) is rising, especially in low- and middle-income countries. The purpose of this review is to summarize existing publications on BC care in Africa. Patients and Methods: A systematic search in MEDLINE and smaller databases was carried out to identify African studies on BC treatment, and an additional PubMed search was performed for relevant topics on BC care. Results: A total of 219 publications, mainly from North and West Africa, were found by systematic search. We also selected articles on BC epidemiology, risk factors, clinical presentation, and cancer control in Africa. Conclusions: Publications on BC treatment are mostly from hospital case series. Evidence on treatment from prospective randomized trials that address the specific characteristics of African patients is lacking. The epidemiologic data shows rising incidences in Africa. The prevalence of risk factors is changing by age group, geographic region, and over time. The clinical picture of BC differs from that of Western countries due to the high proportion of young patients (on account of the African population with a high proportion of young people) and late presentation. Global collaborative efforts are needed to address the rising need for improved BC care in Africa.

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A phase 2 study of the combination of gemcitabine and cisplatin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines with/ without taxanes

Abstract: The results of this study indicate that gemcitabine and cisplatin were active and generally well tolerated in pretreated patients with locally advanced or metastatic breast cancer.

Cited by 7 publications

References 11 publications

Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways

Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways

High-throughput screen identifies disulfiram as a potential therapeutic for triple-negative breast cancer cells: Interaction with IQ motif-containing factors

A Review on Breast Cancer Care in Africa

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