scholarly journals Synergistic action by multi-targeting compounds produces a potent compound combination for human NSCLC both in vitro and in vivo

2014 ◽  
Vol 5 (3) ◽  
pp. e1138-e1138 ◽  
Author(s):  
C Zhang ◽  
S Zhai ◽  
X Li ◽  
Q Zhang ◽  
L Wu ◽  
...  
Nanomedicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 41-54 ◽  
Author(s):  
Xin Jin ◽  
Qing Yang ◽  
Ning Cai ◽  
Zhenhai Zhang

Aim: Lung cancer has a very high incidence rate, and thus, there is an urgent need for novel and effective therapies. Materials & methods: In this study, we proposed a potential treatment option by combining four natural products in liposome systems. Results: In vitro studies indicated that the combination of betulinic acid, parthenolide, honokiol and ginsenoside Rh2 exhibited a synergistic action. When these four natural products were loaded into liposome systems, we observed an increased effect. The relative action was also observed in vivo. The cisplatin group presented obvious kidney damage, whereas both cocktail therapy and cocktail liposome therapy were safer. Conclusion: Therefore, we propose cocktail liposome systems may provide a more efficient and safer treatment for lung cancer.


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13086-13086
Author(s):  
S. Ohtani ◽  
K. Ueda ◽  
G. Jayanchandran ◽  
K. Xu ◽  
J. D. Minna ◽  
...  

13086 Background: 101F6 is a candidate tumor suppressor gene on chromosome 3p21.3, a site of allele loss and genomic alterations were frequently found in many human cancers. We previously showed that enforced expression of wt-101F6 by adenoviral virus significantly inhibited tumor cell growth in 3p21.3-deficient NSCLC cells in vitro and in vivo. How 101F6 exerts this effect is largely unknown. Using a computer-aided structural and functional modeling, we recently identified 101F6 as a member of cytochrome b-561 protein family, which is involved in the regeneration of vitamin C. We hypothesized that under normal physiologic conditions, 101F6 protects cells from oxidative damage by regenerating antioxidant vitamin C and that in 101F6-deficient tumor cells, exogenous 101F6 facilitates vitamin C-mediated cytotoxic H2O2 formation. Methods and Results: We examined endogenous 101F6 expression in human NSCLC cell lines and tissue samples. All normal lung bronchial epithelial cells and fibroblasts but few lung cancers expressed 101F6. We investigated the combined effect of 101F6 and vitamin C on the cell growth: a nanoparticle-mediated wt-101F6 gene transfer plus a sub-pharmacologic concentration of vitamin C synergistically inhibited 3p21.3-deficient NSCLC cell growth but did not affect normal cell growth. We also used a human NSCLC H322 orthotopic lung tumor xenograft mouse model to evaluate the therapeutic efficacy of systemic injection of 101F6 nanoparticles and intraperitoneal injection of vitamin C. The growth of lung tumors was synergistically inhibited by the combination treatment (p<0.001). Furthermore, exogenous 101F6 promoted intracellular vitamin C uptake, leading to the vitamin C-mediated accumulation of H2O2 in the tumor cells, and these two agents synergistically killed the cells through caspase-independent apoptosis and autophagy cell death pathways. Conclusions: The synergistic and selective antitumor effect of 101F6 nanoparticles plus vitamin C may offer a useful tool for lung cancer prevention and intervention. This abstract is supported by grants from NCI (SPORE P50CA70907) and DOD (TARGET, DAMD17002–1-0706). No significant financial relationships to disclose.


Author(s):  
Burton B. Silver ◽  
James C. Hall

Correlative biochemical and structural studies have shown that insulin and Mg++ may act to alter the configuration and also enhance the efficiency of coupled phosphorylation in sonicated fragments of diabetic rat liver mitochondria. The diabetic preparations had consistently lowered P:O ratios which returned to normal values with addition of insulin in vivo or in vitro. Optimum coupling and structural changes with insulin required a Mg++ concentration of 5 × 10−5 M. Insulin remained effective diluted to a concentration of 2 × 10−4 I.U. per ml. Glutathione, bovine serum albumin, and Zn++ were ineffective in producing either coupling or structural changes. There seems to be a synergistic action of insulin and Mg++ in restoring P:O ratios in diabetic particles while simultaneously altering the structure toward normal control appearances. Fragments negatively stained with phosphotungstate indicated that the normal particles had well defined cristae with numerous evenly distributed, stalked subunits, 90 Å in diameter.


2021 ◽  
Vol 14 (5) ◽  
pp. 470
Author(s):  
Nirmala Tilija Pun ◽  
Chul-Ho Jeong

Cancer is incurable because progressive phenotypic and genotypic changes in cancer cells lead to resistance and recurrence. This indicates the need for the development of new drugs or alternative therapeutic strategies. The impediments associated with new drug discovery have necessitated drug repurposing (i.e., the use of old drugs for new therapeutic indications), which is an economical, safe, and efficacious approach as it is emerged from clinical drug development or may even be marketed with a well-established safety profile and optimal dosing. Statins are inhibitors of HMG-CoA reductase in cholesterol biosynthesis and are used in the treatment of hypercholesterolemia, atherosclerosis, and obesity. As cholesterol is linked to the initiation and progression of cancer, statins have been extensively used in cancer therapy with a concept of drug repurposing. Many studies including in vitro and in vivo have shown that statin has been used as monotherapy to inhibit cancer cell proliferation and induce apoptosis. Moreover, it has been used as a combination therapy to mediate synergistic action to overcome anti-cancer drug resistance as well. In this review, the recent explorations are done in vitro, in vivo, and clinical trials to address the action of statin either single or in combination with anti-cancer drugs to improve the chemotherapy of the cancers were discussed. Here, we discussed the emergence of statin as a lipid-lowering drug; its use to inhibit cancer cell proliferation and induction of apoptosis as a monotherapy; and its use in combination with anti-cancer drugs for its synergistic action to overcome anti-cancer drug resistance. Furthermore, we discuss the clinical trials of statins and the current possibilities and limitations of preclinical and clinical investigations.


2020 ◽  
Author(s):  
Danlei Yu ◽  
Yiting Li ◽  
Kevin D-H Sun ◽  
Jiajia Gu ◽  
Zhen Chen ◽  
...  

Abstract Background The oncogenic protein, MET (or c-MET), is involved in the positive regulation of cell survival and proliferation and in mediating acquired resistance to EGFR-TKIs including AZD9291 (osimertinib). Thus, MET inhibition is a promising strategy for overcoming acquired EGFR-TKI resistance due to MET amplification. HQP8361 (MK8033) is a novel and selective MET kinase inhibitor that has completed a phase I clinical trial. The current study focuses on determining the activity and mechanism of action of HQP8361 as a single agent and in combination with AZD9291 against human NSCLC cells, particularly EGFR-mutant NSCLCs with acquired resistance to AZD9291. Methods Drug effects on cell growth in vitro were evaluated by measuring cell number alterations and colony formation and in vivo with mouse xenogtaft models, respectively. Apoptosis was assessed with annexin V/flow cytomentry and protein cleavage. Protein alterations were detected with Western blotting. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene overexpression and knockout were achieved with lentiviral infection and CRISPR/Cas9, respectively. Significance of differences between two tested groups was analyzed with two-sided unpaired Student's t tests. Results The majority of human NSCLC cell lines tested, including those harboring EGFR-activating mutations with acquired resistance to AZD9291, had very low or undetectable levels of MET and p-MET and were insensitive to HQP8361. However, AZD9291-resistant (AR) cell lines derived from the EGFR-mutant HCC827 cell line possessed high levels of MET and p-MET and responded to HQP8361 single agent and particularly to the combination of HQP8361 and AZD9291. The HQP8361 and AZD9291 combination synergistically decreased the survival of these HCC827/AR cell lines with enhanced induction of apoptosis that involved alteration of Bim and Mcl-1 levels via modulating their degradation. Moreover, the combination also very effectively inhibited the growth of HCC827/AR xenografts in nude mice. Conclusions These preclinical findings support the potential of HQP8361 in the treatment of NSCLCs with MET amplification or highly activated MET protein and, when combined with AZD9291, in overcoming acquired resistance to EGFR-TKIs due to MET amplification.


2015 ◽  
Author(s):  
Julia B. Schueler ◽  
Eva Oswald ◽  
Albin Rudisch ◽  
Anne Loehr ◽  
Wolfgang Sommergruber

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Zhiyuan Lou ◽  
Bok‐Soon Lee ◽  
Taekyu Ha ◽  
Yanrui Xu ◽  
Haeng‐Jun Kim ◽  
...  

2019 ◽  
Vol 71 (6) ◽  
pp. 1413-1418
Author(s):  
Erlinda R Ulloa ◽  
Kavindra V Singh ◽  
Matthew Geriak ◽  
Fadi Haddad ◽  
Barbara E Murray ◽  
...  

Abstract Cefazolin and ertapenem combination therapy was used successfully to salvage 11 cases (6 endocarditis) of persistent methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, including immediate clearance (≤24 hours) in 8 cases. While in vitro synergy was modest, cefazolin plus ertapenem exhibited synergistic action in a rat model of MSSA endocarditis. The combination of cefazolin and ertapenem provides potent in vivo activity against MSSA beyond what is predicted in vitro and warrants further clinical study in the treatment of refractory MSSA bacteremia and endocarditis.


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