Steroid receptor RNA activator gene footprint in the progression and drug resistance of colorectal cancer through oxidative phosphorylation pathway

Life Sciences ◽  
2021 ◽  
pp. 119950
Author(s):  
Mohammad Mahdevar ◽  
Jafar Vatandoost ◽  
Farzad Seyed Forootan ◽  
Abbas Kiani-Esfahani ◽  
Maryam Esmaeili ◽  
...  
2020 ◽  
Vol 21 ◽  
Author(s):  
Daniel Sur ◽  
Andrei Havasi ◽  
Alecsandra Gorzo ◽  
Claudia Burz

Background: Anti-EGFR monoclonal antibodies (mAbs) have become a relevant solution for the treatment of patients with metastatic colorectal cancer. Current anti-EGFR monoclonal antibodies face a series of problems, including resistance and non-durable response, and RAS and BRAF mutations serve as exclusion criteria for treatment with anti-EGFR mAbs. Advances in molecular tumor profiling and information on subsequent pathways responsible for disease progression and drug resistance helped develop a new generation of anti-EGFR mAbs. These second-generation mAbs have been developed to overcome existing resistance mechanisms and to limit common side effects. For the moment, existing literature suggests that these novel anti-EGFR mAbs are far from finding their way to clinical practice soon. Objective: In this review, we summarize and evaluate current data regarding ongoing research and completed clinical trials for different second-generation anti-EGFR monoclonal antibodies. Conclusion: Anti-EGFR mAbs exhibit efficacy in advanced colorectal cancer, but second-generation mAbs failed to prove their benefit in the treatment of metastatic colorectal cancer. Understanding the biological basis of primary and acquired drug resistance could allow scientists to design better clinical trials and develop improved second-generation mAbs.


2019 ◽  
Vol 20 (12) ◽  
pp. 1217-1226 ◽  
Author(s):  
Arunaksharan Narayanankutty

Background: Phosphoinositide 3-kinase (PI3Ks) is a member of intracellular lipid kinases and involved in the regulation of cellular proliferation, differentiation and survival. Overexpression of the PI3K/Akt/mTOR signalling has been reported in various forms of cancers, especially in colorectal cancers (CRC). Due to their significant roles in the initiation and progression events of colorectal cancer, they are recognized as a striking therapeutic target. Objective: The present review is aimed to provide a detailed outline on the role of PI3K/Akt/mTOR pathway in the initiation and progression events of colorectal cancers as well as its function in drug resistance. Further, the role of PI3K/Akt/mTOR inhibitors alone and in combination with other chemotherapeutic drugs, in alleviating colorectal cancer is also discussed. The review contains preclinical and clinical evidence as well as patent literature of the pathway inhibitors which are natural and synthetic in origin. Methods: The data were obtained from PubMed/Medline databases, Scopus and Google patent literature. Results: PI3K/Akt/mTOR signalling is an important event in colorectal carcinogenesis. In addition, it plays significant roles in acquiring drug resistance as well as metastatic initiation events of CRCs. Several small molecules of natural and synthetic origin have been found to be potent inhibitors of CRCs by effectively downregulating the pathway. Data from various clinical studies also support these pathway inhibitors and several among them are patented. Conclusion: Inhibitors of the PI3K/mTOR pathway have been successful for the treatment of primary and metastatic colorectal cancers, rendering the pathway as a promising clinical cancer therapeutic target.


Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 502
Author(s):  
Virgílio Souza e Silva ◽  
Emne Ali Abdallah ◽  
Angelo Borsarelli Carvalho de Brito ◽  
Alexcia Camila Braun ◽  
Milena Shizue Tariki ◽  
...  

The discovery of predictive biomarkers in metastatic colorectal cancer (mCRC) is essential to improve clinical outcomes. Recent data suggest a potential role of circulating tumor cells (CTCs) as prognostic indicators. We conducted a follow-on analysis from a prospective study of consecutive patients with mCRC. CTC analysis was conducted at two timepoints: baseline (CTC1; before starting chemotherapy), and two months after starting treatment (CTC2). CTC isolation/quantification were completed by ISET® (Rarecells, France). CTC expressions of drug resistance-associated proteins were evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan–Meier method. Seventy-five patients were enrolled from May 2012 to May 2014. A CTC1 cut-off of >1.5 CTCs/mL was associated with an inferior median OS compared to lower values. A difference of CTC2−CTC1 > 5.5 CTCs/mL was associated with a reduced median PFS. By multivariate analysis, CTC1 > 1.5 CTCs/mL was an independent prognostic factor for worse OS. Multi-drug resistance protein-1 (MRP-1) expression was associated with poor median OS. CTC baseline counts, kinetics, and MRP-1 expression were predictive of clinical outcomes. Larger studies are warranted to explore the potential clinical benefit of treating mCRC patients with targeted therapeutic regimens guided by CTC findings.


Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 39
Author(s):  
Crescenzo Massaro ◽  
Elham Safadeh ◽  
Giulia Sgueglia ◽  
Hendrik G. Stunnenberg ◽  
Lucia Altucci ◽  
...  

Despite substantial progress in cancer therapy, colorectal cancer (CRC) is still the third leading cause of cancer death worldwide, mainly due to the acquisition of resistance and disease recurrence in patients. Growing evidence indicates that deregulation of hormone signaling pathways and their cross-talk with other signaling cascades inside CRC cells may have an impact on therapy resistance. MicroRNAs (miRNAs) are small conserved non-coding RNAs thatfunction as negative regulators in many gene expression processes. Key studies have identified miRNA alterations in cancer progression and drug resistance. In this review, we provide a comprehensive overview and assessment of miRNAs role in hormone signaling pathways in CRC drug resistance and their potential as future targets for overcoming resistance to treatment.


2021 ◽  
Author(s):  
Chaochao Ge ◽  
Yuxia Wang ◽  
Yongli Feng ◽  
Senzhen Wang ◽  
Kemeng Zhang ◽  
...  

Gene Reports ◽  
2021 ◽  
pp. 101252
Author(s):  
Forouzan Amerizadeh ◽  
Mehrdad Moetamani-Ahmadi ◽  
Soodabeh Shahidsales ◽  
Farzad Rahmani ◽  
Masoumeh Gharib ◽  
...  

2016 ◽  
Vol 291 (33) ◽  
pp. 17405-17416 ◽  
Author(s):  
Yang Zhang ◽  
Yi Zhang ◽  
Liying Geng ◽  
Haowei Yi ◽  
Wei Huo ◽  
...  

Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. In addition, we demonstrate for the first time that TGFβ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGFβ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGFβ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGFβ/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.


Author(s):  
Suwisit MANMUAN ◽  
Ponwit MANMUAN ◽  
Punyo YOYKAEW ◽  
Piyachat THUETONG ◽  
Patchraporn ASIPONG ◽  
...  

Centella Asiatica has been traditionally used as herbal medicine to treat various disorders, such as ulcers and psoriatic disease. ECa233 is an herbal extract of Centella Asiatica containing madecassoside (46.3 %) and asiaticoside (41.6 %) that shows a highly acceptable safety profile appropriate for drug development and use as an herbal drug for humans. 5-fluorouracil (5-FU) is a chemotherapeutic agent generally known as the first-line chemotherapy for colorectal cancer. Representative combined chemotherapy with 5-FU, namely the FOLFOX regimen (5-FU, leucovorin, oxaliplatin), has been widely used in hospitals and is typically selected as a chemotherapeutic regimen in prescriptions. However, the unresolved problems appearing in clinical situations are the refusal to accept the chemotherapy leading to drug resistance and the severe side effects after being administered intravenously to the entire body. Therefore, the discovery of a novel pure standard agent to enhance the efficacy of 5-FU and overcome this drug resistance still needs to be explored. To assess the pharmacological activity and safety profile of ECa233 is a major goal in cancer drug discovery. ECa233 was evaluated for its anti-cancer, anti-migration, anti-invasive activities and was explored regarding the safety data on normal cells. The results demonstrated that ECa233 effectively inhibited the cell viability, colony forming, and truly inactivated cell migration/invasion through repressive the MMP-9 invasive factor. Pharmacological interaction with 5-FU was synergism in cancer cells and highly safe to normal cell growth. The results suggest that ECa233 could be used as a combinative drug therapy with standard chemotherapy treatment and other medicinal drugs such as a targeted therapy to treat colorectal cancer patients.


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