Molecular Mimics of Classic P-Glycoprotein Inhibitors as Multidrug Resistance Suppressors and Their Synergistic Effect on Paclitaxel

El‐Araby, Moustafa E.; Omar, Abdelsattar M.; Khayat, Maan T.; Assiri, Hanan A.; Al‐Abd, Ahmed M.

doi:10.1371/journal.pone.0168938

Cited by 25 publications

(35 citation statements)

References 51 publications

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“…Currently, Taxol is widely used in the treatment of NSCLC in the clinics. However, many patients have acquired resistance to Taxol, and even those who initially respond will eventually exhibit MDR . We have confirmed that BZML has potent anti‐cancer activity against Taxol‐sensitive or Taxol‐resistant A549 cells through different death modes in vitro .…”

Section: Discussionsupporting

confidence: 54%

“…However, many patients have acquired resistance to Taxol, and even those who initially respond will eventually exhibit MDR. [44][45][46][47] We have confirmed that BZML has potent anti-cancer activity against Taxol-sensitive or Taxol-resistant A549 cells through different death modes in vitro. 10 This paper aimed to evaluate the anticancer activity of BZML in vivo and the mechanism underlying the apoptosis resistance in BZML-treated A549/Taxol cells.…”

Section: Discussionsupporting

confidence: 53%

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Overcoming resistance to mitochondrial apoptosis by BZML‐induced mitotic catastrophe is enhanced by inhibition of autophagy in A549/Taxol cells

Bai

Gao

et al. 2018

Cell Proliferation

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Section: Discussionsupporting

confidence: 54%

Section: Discussionsupporting

confidence: 53%

Overcoming resistance to mitochondrial apoptosis by BZML‐induced mitotic catastrophe is enhanced by inhibition of autophagy in A549/Taxol cells

Bai

Gao

et al. 2018

Cell Proliferation

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“…In the MTX-resistant RNOV cell line, no increased expression of P-gp or ABCB1 was observed, indicating that an atypical resistance mechanism was being observed. A previous study demonstrated that, in cancer cells resistant to cytostatics the mechanism of action of curcumin is to inhibit P-gp in a competitive or allosteric manner (41).…”

Section: Discussionmentioning

confidence: 99%

Expression of genes and proteins of multidrug resistance in gastric cancer cells treated with resveratrol

et al. 2018

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Abstract. Multidrug resistance (MDR) is a notable problem in the use of chemotherapy. Therefore, studies aimed at identifying substances capable of overcoming resistance of cancer cells are required. Examples of these compounds are polyphenols, including resveratrol, that exert a range of various biological activities. The aim of the present study was to demonstrate the effect of 3,5,4'-trihydroxy-trans-stilbene (resveratrol) on the expression of ATP binding cassette subfamily B member 1, Annexin A1 (ANXA1) and thioredoxin (TXN) genes, and the proteins encoded by these genes, which are associated with MDR. The experiments were performed in human gastric cancer cell lines EPG85-257RDB (RDB) and EPG85-257RNOV (RNOV), which are resistant to daunorubicin and mitoxantrone, respectively, in addition to EPG85-257P (control), which is sensitive to cytostatic drugs. Cells were treated with 30 or 50 µM resveratrol for 72 h and changes in the expression levels of the genes were analysed with the use of a reverse transcription-quantitative polymerase chain reaction. The cellular levels of P-glycoprotein (P-gp), ANXA1 and TXN were evaluated using immunofluorescence and western blot analysis. Resveratrol in both concentrations has been shown to have a statistically significant influence on expression of the mentioned genes, compared with untreated cells. In RDB cells, resveratrol reduced the expression level of all analyzed genes, compared with untreated cells. Similar results at the protein level were obtained for P-gp and TXN. In turn, in the RNOV cell line, resveratrol reduced TXN expression at mRNA and protein levels, compared with untreated cells. The results of the present study indicate that resveratrol may reduce the resistance of cancer cells by affecting the expression of a number of the genes and proteins associated with MDR. IntroductionResveratrol belongs to the stilbenoid group of polyphenols, possessing two phenol rings linked to each other by an ethylene bridge (1). In 1940, resveratrol was isolated from the root of Veratrum grandiflorum (1,2). A primary dietary source of resveratrol is red wine, as a very high resveratrol concentration is present in the skin of red grapes (50-100 µg/g) (3). In natural conditions, resveratrol is synthesized by plants in response to external environmental factors, including ultraviolet radiation and heavy metals (3,4). Resveratrol is identified in two isomeric forms, cis and trans-resveratrol ( Fig. 1) (5,6).The trans form is dominant in terms of its prevalence and biological activity (7). The hydrophobic nature of resveratrol considerably contributes to its limited bioavailability (8).Owing to the varied biological activity of resveratrol, it has been the subject of numerous studies aimed at revealing its health-enhancing properties, and its use in prevention and treatment of many diseases (1,3,5,9). The results of in vitro and in vivo studies have proved that resveratrol exhibits anticancer activity at all three stages of the oncogenic process: initiation, promotion and progr...

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“…The synthetic pathway, described in scheme 1 utilized Erlenmeyer chemistry for azlactone synthesis. [14] In this scheme, non-commercially available cinnamic acid analogues 2 were prepared by condensation of the corresponding aldehyde with malonic acid. [15] After conversion to the hippuric acid analogues (3), cyclocondensation was affected by their reaction with the corresponding aldehydes to afford the 2-arylvinyl-4benzylidene-5-oxazolinone derivatives (azlactones, 4) under Erlenmeyer conditions.…”

Section: Chemical Synthesis Of 2-cinnamamido-n-substituted-cinnamamidmentioning

confidence: 99%

“…The compound with the highest activity in this subset was the N- (1-adamantyl) analogue (1505, Entry 4) with IC50 = 14.7 ± 0.3 µM, but with poor solubility (ClogP 6.08), while compound 1512 (Entry 2) with moderate activities (IC50 = 32.0 ± 2.6 µM) showed better solubility profile (CLogP 4.48). Importantly, 1512 showed significantly low cancer cell resistance (R-value = 8.2%), [14] and high selectivity in killing cancer cells (HCT-116, Caco-2 and HT-29) versus highly proliferative normal cells (C-166 mouse skin fibroblasts) (Figure 3). Based on 1512 favorable pharmacologic and physicochemical properties, it was selected as a new lead for the second subset of compounds (Entries 23 to 56).…”

Section: Antiproliferative Activities Of Bis-cinnamamide Derivativesmentioning

confidence: 99%

Discovery, optimization, and cellular activities of 2-(aroylamino)cinnamamide derivatives against colon cancer cells

El-Haggar

Omar

Abdelghany

et al. 2019

Preprint

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Curcumin and trans-cinnamaldehyde are acrolein-based Michael acceptor compounds that are commonly found in domestic condiments, and known to cause cancer cell death via redox mechanisms. Based on the structural features of these compounds we designed and synthesized several 2-cinnamamido-N-substitutedcinnamamide (bis-cinnamamide) compounds. One of the derivatives, (Z)-2-[(E)cinnamamido]-3-phenyl-N-propylacrylamide (1512) showed a moderate antiproliferative potency (HT116 cell line inhibition of 32.0 µM ± 2.6) with proven cellular activities leading to apoptosis. Importantly, 1512 exhibited good selectivity toxicity on cancer cells over noncancerous cells (IC50 of C-166 cell lines >100 µM), and low cancer cell resistance at 100 µM dose (growth rate 10.1±1.1%). We subsequently carried out structure activity relationship studies with 1512. Derivatives with electron rich moiety at the aryl ring of the 2-aminocinnamaide moiety exhibited strong antiproliferative action while electron withdrawing groups caused loss of activity. Our most promising compound, 4112 [(Z)-3-(1H-indol-3-yl)-N-propyl-2-[(E)-3-(thien-2-yl)propenamido)propenamide] killed cancer cells at IC50 = 0.89 ± 0.04 µM (Caco-2), 2.85 ± 1.5 (HCT-116) and 1.65 ± 0.07 (HT-29), while exhibiting much weaker potency on C-166 and BHK normal cell lines (IC50 = 71 ± 5.12 and 77.6 ± 6.2 µM, respectively). Cellular studies towards identifying the compounds mechanism of cytotoxic activities revealed that apoptotic induction occurs in part due to oxidative stress. Importantly, the compounds showed inhibition of cancer stem cells that are critical for maintaining the potential for self-renewal and stemness. The results presented here show discovery of Michael addition compounds that potently kill cancer cells by a defined mechanism, with minimal effect on normal noncancerous cell. * * 7.79 Hz, 2H), 7.55 (d, J = 7.79 Hz, 2H), 7.51 (d, J = 15.57 Hz, 1H), 7.49-7.44 (m, 2 H), 7.42 (d, J = 7.27 Hz, 1H), 7.39 (t, J = 7.79 Hz, 2H), 7.29-7.34 (m, 1 H), 6.88 (d, J = 16.09 Hz, 1 H) 7.05 (s, 1H), 4.65 (t, J = 5.71 Hz, 1 H), 3.47 (q, J = 5.88 Hz, 2 H), 3.24 (q, J = 6.23 Hz, 2 H). LC-MS (ESI) RT = 3.48 min, m/z 337.0 [M + H] + . N-[(Z)-3-morpholino-3-oxo-1-phenylprop-1-en-2-yl]cinnamamide (1536)This compound was prepared according to the procedure described for the synthesis of 1502 starting from oxazolone 3 (2 mmol, 0.554 g) and morpholine (4 mmol, 0.39 mL). The product 1536 was an off-white power, (.514 g, 71%), Mp. 185 °C; 1H NMR (600 MHz, DMSO-d6) δH 10.07 (s, 1H), 7.56 -7.63 (m, 6H), 7.40 -7.48 (m, 6H), 7.27 -7.36 (m, 1H), 6.93 (d, J = 15.81 Hz, 1H), 6.19 (s, 1H), 3.53 (br. s., 4H), 3.35 (br. s., 4H). N-[(Z)-3-(1-pyyrrolidinyl)-3-oxo-1-phenylprop-1-en-2-yl]cinnamamide (1555)This compound was prepared according to the procedure described for the synthesis of 1502 starting from oxazolone 3 (2 mmol, 0.554 g) and pyrrolidine (2mmol, 0.165 mL).The product 1555 was a white power, (0.580 g, 84%), Mp. 194 °C; 1 H NMR (600 MHz, DMSO-d6) δH 10.00 (s, 1H), 7.52 -7.64 (m, 6H), 7.37 -7.49 (m...

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Molecular Mimics of Classic P-Glycoprotein Inhibitors as Multidrug Resistance Suppressors and Their Synergistic Effect on Paclitaxel

Cited by 25 publications

References 51 publications

Overcoming resistance to mitochondrial apoptosis by BZML‐induced mitotic catastrophe is enhanced by inhibition of autophagy in A549/Taxol cells

Overcoming resistance to mitochondrial apoptosis by BZML‐induced mitotic catastrophe is enhanced by inhibition of autophagy in A549/Taxol cells

Expression of genes and proteins of multidrug resistance in gastric cancer cells treated with resveratrol

Discovery, optimization, and cellular activities of 2-(aroylamino)cinnamamide derivatives against colon cancer cells

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