apoptotic induction
Recently Published Documents


TOTAL DOCUMENTS

145
(FIVE YEARS 44)

H-INDEX

22
(FIVE YEARS 5)

2021 ◽  
Vol 9 ◽  
Author(s):  
Yingpinyapat Kittirat ◽  
Jutarop Phetcharaburanin ◽  
Bundit Promraksa ◽  
Thanaporn Kulthawatsiri ◽  
Arporn Wangwiwatsin ◽  
...  

Pyrvinium pamoate (PP), an FDA-approved anthelmintic drug, has been validated as a highly potent anti-cancer agent and patented recently as a potential chemotherapeutic drug for various cancers. The aims of this study were, therefore, to investigate the ability of PP in anti-proliferative activity and focused on the lipid profiles revealing the alteration of specific lipid species in the liver fluke Opisthorchis viverrini (Ov)-associated cholangiocarcinoma (CCA) cells. PP inhibited CCA cell viability through suppressing mitochondrial membrane potential (MMP) and ATP productions, leading to apoptotic cell death. Liquid chromatography-mass spectrometry combined with chemometrics was performed to investigate lipid alteration during PP-induced apoptosis. The lipidomic analyses showed the altered lipid signatures of CCA cell types including S-acetyldihydrolipoamide, methylselenopyruvate, and triglycerides that were increased in PP-treated CCA cells. In contrast, the levels of sphinganine and phosphatidylinositol were lower in the PP-treated group compared with its counterpart. The orthogonal partial-least squares regression analysis revealed that PP-induced MMP dysfunction, leading to remarkably reduced ATP level, was significantly associated with triglyceride (TG) accumulation observed in PP-treated CCA cells. Our findings indicate that PP could suppress the MMP function, which causes inhibition of CCA cell viability through lipid production, resulting in apoptotic induction in CCA cells. These findings provide an anti-cancer mechanism of PP under apoptotic induction ability that may serve as the alternative approach for CCA treatment.


Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7412
Author(s):  
Eric Chekwube Aniogo ◽  
Blassan P. George ◽  
Heidi Abrahamse

Multidrug resistance (MDR) has posed a significant threat to cancer treatment and has led to the emergence of a new therapeutic regime of photodynamic therapy (PDT) to curb the menace. The PDT modality employs a photosensitiser (PS), excited at a specific wavelength of light to kill cancer cells. In the present study, we used a zinc phthalocyanine tetrasulfonic acid PS to mediate the photodynamic killing of MCF-7 cells overexpressed with P-glycoprotein (P-gp) and investigate the response to cell death induction. After photodynamic treatment, MCF-7 cells undergo cell death, and indicators like Annexin V/PI staining, DNA fragmentation, and measurement of apoptotic protein expression were investigated. Results showed increased externalisation of phosphatidylserine protein, measured as a percentage in flow cytometry indicative of apoptotic induction. This expression was significant (p < 0.006) for the untreated control cells, and there was no detection of DNA fragments after a laser fluence of 20 J/cm2. In addition, a statistically significant difference (p < 0.05) was seen in caspase 8 activity and Bax protein expression. These findings were indicative of apoptotic induction and thus seem to represent the extrinsic apoptotic pathway. This study shows the role of PDT in the treatment of a resistant phenotype breast cancer.


Author(s):  
Khuzama A. Aljunidee ◽  
Sanaa K. Bardaweel

Abstract Objectives To evaluate the anticancer effects of calcitriol and cholecalciferol against different cell lines of breast cancer in monotherapy settings and in combination with raloxifene. Methods The antiproliferative, anti-migratory, and apoptotic induction effects were assessed by MTT, wound healing, and flow cytometry assays, respectively. Results Calcitriol and cholecalciferol exhibited antiproliferative effects against T47D, MCF-7, and MDA-MB-231 in a time and concentration-dependent manner. The IC50 values of calcitriol were in the range of 0.05–0.25 μM while that for cholecalciferol were in the range of 3–100 μM. Furthermore, the results showed that calcitriol and cholecalciferol exhibited anti-migratory effects on MDA-MB-231, an apoptotic induction effect on MCF-7 cells, and a synergistic effect when combined with raloxifene. Conclusions Calcitriol and cholecalciferol exhibited anticancer effects and may be used as chemosensitizers.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2669-2669
Author(s):  
Chad C Bjorklund ◽  
Michael Amatangelo ◽  
Jian Kang ◽  
Hsiling Chiu ◽  
Archana Mukhopadhyay ◽  
...  

Abstract Background: Pomalidomide (POM) is an established agent in relapsed/refractory (R/R) multiple myeloma (MM). CC-92480, a novel cereblon E3 ligase modulator (CELMoD ®) agent, is being investigated in R/R MM patients in combination with the proteasome inhibitor (PI) bortezomib (BTZ) and steroid dexamethasone (DEX) (NCT03374085/NCT03989414). Previously, we showed mechanistic synergy of POM/BTZ/DEX in MM cell line models (Bjorklund et al). Here we analyzed the cell autonomous cytotoxic activities of CC-92480 or POM alone and in combination with BTZ/DEX to compare and differentiate their mechanisms of action (MOA). Results: Comparative analysis of the anti-proliferative activity against H929 and MM1.S cell lines revealed that CC-92480 demonstrated a more potent inhibition of proliferation by 100-fold lower dose compared to POM. Combination experiments utilizing a titration of POM or CC-92480 in combination with a 1 hr BTZ pulse, to mimic the clinical pharmacokinetics (+/- DEX co-treatment) showed an enhancement of antiproliferative capacity in both doublet and triplet combinations compared to single agents. Combination indices for POM/BTZ/DEX or CC-92480/BTZ/DEX resulted in values &lt;1 for most combinations indicating a synergistic effect. Additionally, POM or CC-92480 in combination with BTZ or DEX, or in triplet combinations increased induction of apoptosis (&gt;90% for each triplet compared to POM (20%) and CC-92480 (40%). Flow cytometric analysis of Aiolos and Ikaros protein level in MM cells treated with POM/BTZ/DEX or CC-92480/BTZ/DEX resulted in a slight kinetic delay in substrate depletion at early time points (1-4 hr), where the effect is less apparent with CC-92480, and indistinguishable at 24 hr compared to single agent POM or CC-92480 in the clinically relevant concentrations. We performed transcriptomic analyses of H929 cells treated with POM/BTZ/DEX or CC-92480/BTZ/DEX for 24 hrs to identify key pathways responsible for the observed synergistic combination effect. Common pathways dysregulated by POM or CC-92480 included previously identified interferon, protein homeostasis and proliferation gene sets. Gene set enrichment analysis (GSEA) showed many significant pathway differences when comparing the triplets, including general cell cycle progression, cell division and chromatin segregation. Interestingly, genes involved in negative regulation of G 2/M transition were identified as one of the most significant differences between POM/BTZ/DEX and CC-92480/BTZ/DEX. To understand how these pathways contributed to cell cycle effects and apoptosis, we assessed DNA fragmentation by TUNEL in conjunction with cell cycle flow cytometry to examine cell cycle specific apoptotic induction. Temporal assessment (6, 12, 18, 24, and 48 hr treatments) demonstrated accumulation of BrdU incorporation in all cell cycle phases when treated with POM/BTZ/DEX or CC-92480/BTZ/DEX indicating cell death was occurring within all phases. However, there was a marked enhancement of G 2/M BrdU incorporation (80% vs. 40% of G 2/M population) at 18-24 hr when treated with CC-92480/BTZ/DEX compared to POM/BTZ/DEX, or other single agent treatments. Additionally, G 2/M transition-dependent cyclins A and B were shown to be dysregulated by CC-92480. These data indicate that CC-92480 potentiates a G 2/M arrest in combination with BTZ in MM cells. Conclusions: These results demonstrate that CC-92480 alone or in combination with BTZ/DEX elicits a more potent cytotoxic effect on MM cells compared to POM. Importantly, the combination of either POM or CC-92480 with a PI, like BTZ, does not appreciatively affect single agent MOA. We have also identified a key differentiating mechanism of cell autonomous activity for CC-92480 in combination with BTZ/DEX where MM cells enhance apoptotic induction at the G 2/M stage compared to POM. Clinically, this added mechanistic difference suggests a more cytotoxic response in patients treated with CC-92480/BTZ/DEX compared to POM/BTZ/DEX. Disclosures Bjorklund: BMS: Current Employment, Current equity holder in publicly-traded company. Amatangelo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kang: BMS: Current equity holder in publicly-traded company. Chiu: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Pourdehnad: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: No royalty. Hagner: BMS: Current Employment, Current equity holder in publicly-traded company. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.


2021 ◽  
Vol 8 (3) ◽  
Author(s):  
G A Gowthami ◽  
Subhankar Das ◽  
Yalpi Karthik ◽  
I K Manjula

Endophytes contribute to the synthesis of significant metabolites in symbiotic association with their host plants. On considering the medicinal importance of the prominent tree species Pajanelia longifolia (Willd.) K. Schuman, the study was conducted to isolate and identify the endophytic bacteria and fungi for their bioactivity. The isolation of endophytic bacteria and fungi were performed by surface sterilisation of the stem and leaf samples of P. longifolia. The obtained bacterial and fungal endophytic isolates were maintained in nutrient agar and Potato Dextrose Agar (PDA) media and were examined for colony morphology and microscopic appearances with varied biochemical characterisations. Furthermore, both the fungal and bacterial isolates were subjected to solvent extractions to evaluate antibacterial activity. Also, anti-proliferative effects due to apoptotic induction by the endophytic fungal extracts were checked against proliferative yeast cells. Moreover, endophytic bacteria belonging to Enterococcaceae had shown antibacterial activity against Salmonella species. In the present study, fungal species belonging to Cladosporium predominantly found to inhabit as endophytic fungi in the plant samples. Also, this particular fungus among other selected endophytic fungi attributed to causing effective anti-proliferative activity. The endophytic bacteria belonging to Enterococcus and Micrococcus genera showed significant antimicrobial activity against Salmonella typhimurium (ATCC 23564).


2021 ◽  
Author(s):  
Rovingaile Kriska Ponce ◽  
Nicholas J Thomas ◽  
Nam Q Bui ◽  
Tadashi Kondo ◽  
Ross A Okimoto

CIC-DUX4 rearrangements define an aggressive and chemotherapy-insensitive subset of undifferentiated sarcomas. The CIC-DUX4 fusion drives oncogenesis through direct transcriptional upregulation of cell cycle and DNA replication genes. Notably, CIC-DUX4-mediated CCNE1 upregulation compromises the G1/S transition, conferring a potential survival dependence on the G2/M cell cycle checkpoint. Through an integrative transcriptional and kinase activity screen using patient-derived specimens, we now show that CIC-DUX4 sarcomas depend on the G2/M checkpoint regulator, WEE1, as an adaptive survival mechanism. Specifically, CIC-DUX4 sarcomas depend on WEE1 activity to limit DNA damage and unscheduled mitotic entry. Consequently, genetic or pharmacologic WEE1 inhibition in vitro and in vivo leads to rapid DNA damage-associated apoptotic induction of patient-derived CIC-DUX4 sarcomas. Thus, we identify WEE1 as an actionable therapeutic vulnerability in CIC-DUX4 sarcomas.


Polyhedron ◽  
2021 ◽  
pp. 115205
Author(s):  
Azadeh Mirzaahmadi ◽  
Seyed Abolfazl Hosseini-Yazdi ◽  
Majid Mahdavi ◽  
Michal Dusek ◽  
Valcav. Eigner ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document