scholarly journals Insights into an Immunotherapeutic Approach to Combat Multidrug Resistance in Hepatocellular Carcinoma

2021 ◽  
Vol 14 (7) ◽  
pp. 656
Author(s):  
Aswathy R. Devan ◽  
Ayana R. Kumar ◽  
Bhagyalakshmi Nair ◽  
Nikhil Ponnoor Anto ◽  
Amitha Muraleedharan ◽  
...  

Hepatocellular carcinoma (HCC) has emerged as one of the most lethal cancers worldwide because of its high refractoriness and multi-drug resistance to existing chemotherapies, which leads to poor patient survival. Novel pharmacological strategies to tackle HCC are based on oral multi-kinase inhibitors like sorafenib; however, the clinical use of the drug is restricted due to the limited survival rate and significant side effects, suggesting the existence of a primary or/and acquired drug-resistance mechanism. Because of this hurdle, HCC patients are forced through incomplete therapy. Although multiple approaches have been employed in parallel to overcome multidrug resistance (MDR), the results are varying with insignificant outcomes. In the past decade, cancer immunotherapy has emerged as a breakthrough approach and has played a critical role in HCC treatment. The liver is the main immune organ of the lymphatic system. Researchers utilize immunotherapy because immune evasion is considered a major reason for rapid HCC progression. Moreover, the immune response can be augmented and sustained, thus preventing cancer relapse over the post-treatment period. In this review, we provide detailed insights into the immunotherapeutic approaches to combat MDR by focusing on HCC, together with challenges in clinical translation.

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Carolina Soekmadji ◽  
Colleen C. Nelson

Emerging evidence has shown that the extracellular vesicles (EVs) regulate various biological processes and can control cell proliferation and survival, as well as being involved in normal cell development and diseases such as cancers. In cancer treatment, development of acquired drug resistance phenotype is a serious issue. Recently it has been shown that the presence of multidrug resistance proteins such as Pgp-1 and enrichment of the lipid ceramide in EVs could have a role in mediating drug resistance. EVs could also mediate multidrug resistance through uptake of drugs in vesicles and thus limit the bioavailability of drugs to treat cancer cells. In this review, we discussed the emerging evidence of the role EVs play in mediating drug resistance in cancers and in particular the role of EVs mediating drug resistance in advanced prostate cancer. The role of EV-associated multidrug resistance proteins, miRNA, mRNA, and lipid as well as the potential interaction(s) among these factors was probed. Lastly, we provide an overview of the current available treatments for advanced prostate cancer, considering where EVs may mediate the development of resistance against these drugs.


2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Lakshana Sreenivasan ◽  
Hui Wang ◽  
Shyong Quin Yap ◽  
Pascal Leclair ◽  
Anthony Tam ◽  
...  

AbstractMedulloblastoma (MB) is a high-grade pediatric brain malignancy that originates from neuronal precursors located in the posterior cranial fossa. In this study, we evaluated the role of STAT3 and IL-6 in a tumor microenvironment mediated drug resistance in human MBs. We established that the Group 3 MB cell line, Med8A, is chemosensitive (hence Med8A-S), and this is correlated with a basal low phosphorylated state of STAT3, while treatment with IL-6 induced robust increases in pY705-STAT3. Via incremental selection with vincristine, we derived the stably chemoresistant variant, Med8A-R, that exhibited multi-drug resistance, enhanced IL-6 induced pY705-STAT3 levels, and increased IL6R expression. Consequently, abrogation of STAT3 or IL6R expression in Med8A-R led to restored chemosensitivity to vincristine, highlighting a prominent role for canonical IL-6/STAT3 signaling in acquired drug resistance. Furthermore, Med8A-S subjected to conditioning exposure with IL-6, termed Med8A-IL6+ cells, exhibited enhanced vincristine resistance, increased expression of pY705-STAT3 and IL6R, and increased secretion of IL-6. When cocultured with Med8A-IL6+ cells, Med8A-S cells exhibited increased pY705-STAT3 and increased IL-6 secretion, suggesting a cytokine feedback loop responsible for amplifying STAT3 activity. Similar IL-6 induced phenomena were also observed in the Group 3 MB cell lines, D283 and D341, including increased pY705-STAT3, drug resistance, IL-6 secretion and IL6R expression. Our study unveiled autocrine IL-6 as a promoter of STAT3 signaling in development of drug resistance, and suggests therapeutic benefits for targeting the IL-6/STAT3 signaling axis in Group 3 MBs.


2020 ◽  
Vol 11 ◽  
Author(s):  
Yingying Kou ◽  
Bending Tong ◽  
Weiqing Wu ◽  
Xiangqing Liao ◽  
Min Zhao

Gastric cancer is one of the most common malignancies ranks as the second leading cause of cancer-related mortality in the world. Cisplatin (DDP) is commonly used for gastric cancer treatment, whereas recurrence and metastasis are common because of intrinsic and acquired DDP-resistance. The aim of this study is to examine the effects of berberine on the DDP-resistance in gastric cancer and explore the underling mechanisms. In this study, we established the DDP-resistant gastric cancer cells, where the IC50 values of DDP in the BGC-823/DDP and SGC-7901/DDP were significantly higher than that in the corresponding parental cells. Berberine could concentration-dependently inhibited the cell viability of BGC-823 and SGC-7901 cells; while the inhibitory effects of berberine on the cell viability were largely attenuated in the DDP-resistant cells. Berberine pre-treatment significantly sensitized BGC-823/DDP and SGC-7901/DDP cells to DDP. Furthermore, berberine treatment concentration-dependently down-regulated the multidrug resistance-associated protein 1 and multi-drug resistance-1 protein levels in the BGC-823/DDP and SGC7901/DDP cells. Interestingly, the cell apoptosis of BGC-823/DDP and SGC-7901/DDP cells was significantly enhanced by co-treatment with berberine and DDP. The results from animals also showed that berberine treatment sensitized SGC-7901/DDP cells to DDP in vivo. Mechanistically, berberine significantly suppressed the PI3K/AKT/mTOR in the BGC-823/DDP and SGC-7901/DDP cells treated with DDP. In conclusion, we observed that berberine sensitizes gastric cancer cells to DDP. Further mechanistic findings suggested that berberine-mediated DDP-sensitivity may be associated with reduced expression of drug transporters (multi-drug resistance-1 and multidrug resistance-associated protein 1), enhanced apoptosis and repressed PI3K/AKT/mTOR signaling.


2012 ◽  
Vol 4 (1) ◽  
pp. 36 ◽  
Author(s):  
Ian May ◽  
Maha Abu-Khdeir ◽  
Roland Alexander Blackwood

Infections caused by <em>Pseudomonas aeruginosa </em>are becoming more common and increasingly more difficult to treat due to the continued development of drug resistance. While sensitivity to colistin (polymyxin E) is well known, it is frequently avoided due to concerns of nephrotoxicity. Reported here is a case of a multi-drug resistance pseudomonal typhlitis, bacteremia and pleural cavity infection that required significant intensive care, and serial abdominal washouts. Intra-peritoneal tobramycin in combination with broad-spectrum intravenous antibiotics including colistin were used. Several instillations of tobramycin into the abdominal cavity along with concomitant IV administration of colistin, ceftazidime and tobramycin and<em> per os</em> colistin, tobramycin and nystatin resulted in the clearance of the pseudomonal infection without any evidence of toxicity from the treatment. Intra-abdominal tobramycin with parenteral colistin therapy can be used in complicated clinical settings with appropriate nephroprotection.


2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Lai Wei ◽  
Derek Lee ◽  
Cheuk-Ting Law ◽  
Misty Shuo Zhang ◽  
Jialing Shen ◽  
...  

Abstract Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common. By using genome-wide CRISPR/Cas9 library screening, we identify phosphoglycerate dehydrogenase (PHGDH), the first committed enzyme in the serine synthesis pathway (SSP), as a critical driver for Sorafenib resistance. Sorafenib treatment activates SSP by inducing PHGDH expression. With RNAi knockdown and CRISPR/Cas9 knockout models, we show that inactivation of PHGDH paralyzes the SSP and reduce the production of αKG, serine, and NADPH. Concomitantly, inactivation of PHGDH elevates ROS level and induces HCC apoptosis upon Sorafenib treatment. More strikingly, treatment of PHGDH inhibitor NCT-503 works synergistically with Sorafenib to abolish HCC growth in vivo. Similar findings are also obtained in other FDA-approved tyrosine kinase inhibitors (TKIs), including Regorafenib or Lenvatinib. In summary, our results demonstrate that targeting PHGDH is an effective approach to overcome TKI drug resistance in HCC.


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