cell sensitivity
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2021 ◽  
Vol 13 (623) ◽  
Author(s):  
Afroditi Katsarou ◽  
Maria Sjöstrand ◽  
Jyoti Naik ◽  
Jorge Mansilla-Soto ◽  
Dionysia Kefala ◽  
...  

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Tianyu Sun ◽  
Jingge Zhang ◽  
Xiaoqing Fan ◽  
Tan Long ◽  
Shaolin Tao ◽  
...  

Reduced sensitivity to chemotherapeutic drugs is almost inevitable in lung adenocarcinoma patients. Thus, understanding the relevant mechanisms is urgent. Positive cofactor 4 (PC4) was at first revealed to be a coactivator of basal transcription. Previous research has shown that PC4 participates in various cellular processes in normal and malignant cells. However, it is still unknown whether PC4 participates in altering the lung adenocarcinoma cell sensitivity to chemotherapy, and the relevant mechanisms remain to be explained. In this study, we discovered that PC4 was overexpressed in cisplatin-resistant lung adenocarcinoma cells. PC4 decreased cisplatin’s cytotoxic effects on lung adenocarcinoma in vivo and in vitro. Furthermore, PC4 positively correlated with SOX9 in multiple cancers. PC4 was an upstream regulator of SOX9 in lung adenocarcinoma. Furthermore, PC4 mediated lung adenocarcinoma cell sensitivity to the HIF-PH inhibitor DMOG and the mTOR inhibitor rapamycin, and PC4 mediated the synergistic effect of DMOG and cisplatin. Finally, PC4 destabilized HIF-1α upon cisplatin treatment. Our research showed that PC4 participates in mediating lung adenocarcinoma cell sensitivity to multiple drugs. Mechanistically, PC4 governs multiple downstream pathways associated with chemotherapy resistance, including the SOX9 and HIF-1α pathways. Thus, PC4 is a promising chemotherapeutic target in lung adenocarcinoma.


2021 ◽  
Vol 13 (47) ◽  
pp. 125-129
Author(s):  
Andrea Maria Signorini

A homeopathic widespread belief is that the inversion of effect of the drugs in homeopathic medical practice is due to dilution or very low doses, but there are many homeopathic incoherencies. For example the first conception of the similia principle was obtained through planned, small sample, clinical experiments with ponderal/pharmacological doses in healthy and diseased subjects1. Furthermore the classical foundations of the similia principle in Organon2, the primary and secondary actions of drugs, were thought to be connected with opposite, time-dependent reactions of the body to high doses and the inversion of effect was seen in temporal sequence after a strong dose and not after changes of doses, so the idea that dilutions are responsible for inversion of effects is not suitable to the classical theory. And lastly homeopathic provings or pathogenetic trials have frequently mixed, unregarded to the doses, occasional toxicological symptoms and symptoms obtained through diluted substances3, reinforcing the idea that, on healthy subjects, in several cases many substances produce the same symptoms in pharmacological or infinitesimal doses. So at least the dose-dependent inversion of effect is not generalized in a great part of the collected symptoms. Biological foundations to similia principle have to be searched in other directions4, as in different sensitivity to drugs between health and disease, or in different time-dependent effect of drugs on specific, but different, cell sensitivity set point. In the vision described here both these possibilities represent the same phenomenon of altered cell sensitivity. It is aim of this article to show that the original hahnemannian idea to explain homeopathic similia principle starting from a pharmacological and biological point of view with ponderal doses, seems correct, rationally comprehensible and based on modern knowledges. The three pharmacologic examples that best illustrate this reasoning, coffe, opium and wine, will be discussed.


Author(s):  
Rupam Ghosh ◽  
Yiling Xiao ◽  
Jaka Kragelj ◽  
Kendra K. Frederick

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4761
Author(s):  
Delphine Morales ◽  
Pascale Vigneron ◽  
Ines Ferreira ◽  
Warda Hamitou ◽  
Mikael Magnano ◽  
...  

The sensitivity of melanoma cells to targeted therapy compounds depends on the tumor microenvironment. Three-dimensional (3D) in vitro coculture systems better reflect the native structural architecture of tissues and are ideal for investigating cellular interactions modulating cell sensitivity to drugs. Metastatic melanoma (MM) cells (SK-MEL-28 BRAF V600E mutant and SK-MEL-2 BRAF wt) were cultured as a monolayer (2D) or cocultured on 3D dermal equivalents (with fibroblasts) and treated with a BRAFi (vemurafenib) combined with a MEK inhibitor (MEKi, cobimetinib). The drug combination efficiently inhibited 2D and 3D MM cell proliferation and survival regardless of their BRAF status. Two-dimensional and three-dimensional cancer-associated fibroblasts (CAFs), isolated from a cutaneous MM biopsy, were also sensitive to the targeted therapy. Conditioned media obtained from healthy dermal fibroblasts or CAFs modulated the MM cell’s response differently to the treatment: while supernatants from healthy fibroblasts potentialized the efficiency of drugs on MM, those from CAFs tended to increase cell survival. Our data indicate that the secretory profiles of fibroblasts influence MM sensitivity to the combined vemurafenib and cobimetinib treatment and highlight the need for 3D in vitro cocultures representing the complex crosstalk between melanoma and CAFs during preclinical studies of drugs.


BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Se-Kyeong Jang ◽  
Sung-Eun Hong ◽  
Da-Hee Lee ◽  
Ji-Young Kim ◽  
Ji Yea Kim ◽  
...  

Abstract Background Although the major anticancer effect of metformin involves AMPK-dependent or AMPK-independent mTORC1 inhibition, the mechanisms of action are still not fully understood. Methods To investigate the molecular mechanisms underlying the effect of metformin on the mTORC1 inhibition, MTT assay, RT-PCR, and western blot analysis were performed. Results Metformin induced the expression of ATF4, REDD1, and Sestrin2 concomitant with its inhibition of mTORC1 activity. Treatment with REDD1 or Sestrin2 siRNA reversed the mTORC1 inhibition induced by metformin, indicating that REDD1 and Sestrin2 are important for the inhibition of mTORC1 triggered by metformin treatment. Moreover, REDD1- and Sestrin2-mediated mTORC1 inhibition in response to metformin was independent of AMPK activation. Additionally, lapatinib enhances cell sensitivity to metformin, and knockdown of REDD1 and Sestrin2 decreased cell sensitivity to metformin and lapatinib. Conclusions ATF4-induced REDD1 and Sestrin2 expression in response to metformin plays an important role in mTORC1 inhibition independent of AMPK activation, and this signalling pathway could have therapeutic value.


Author(s):  
Juraj Hlavaty ◽  
Reinhard Ertl ◽  
Tewodros Abere Mekuria ◽  
Barbara Rütgen ◽  
Hajime Tsujimoto ◽  
...  

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