Development of novel synthesized phthalazinone-based PARP-1 inhibitors with apoptosis inducing mechanism in lung cancer

Almahli, Hadia; Hadchity, Élie; Jaballah, Maiy; Daher, Racha; Ghabbour, Hazem A.; Kabil, Maha M.; Al-Shakliah, Nasser S.; Eldehna, Wagdy M.

doi:10.1016/j.bioorg.2018.01.034

Cited by 64 publications

(34 citation statements)

References 40 publications

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“…28 It is activated by recognizing DNA fragments with damaged structure and is considered as DNA damage receptor. 29 Wu et al identified that PARP inhibitor induces leukemia cell apoptosis via DNA damage and reverses leukemia cell adriamycin resistance. 30 Our data have shown that combined therapy with leonurine and cisplatin elevated the PARP protein expression and accelerated the DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Leonurine Promotes Cisplatin Sensitivity in Human Cervical Cancer Cells Through Increasing Apoptosis and Inhibiting Drug-Resistant Proteins

Lin

Pan

et al. 2020

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Background: Cisplatin-based neoadjuvant chemotherapy and concurrent radiotherapy and chemotherapy are the main treatment for advanced cervical cancer. However, the development of multidrug resistance (MDR) leads to chemotherapy failure, tumor recurrence and poor survival. In this research, we investigated the effect and corresponding mechanism of leonurine on cisplatin sensitivity of cervical cancer cells. Methods: Anti-cervical cancer efficacy of leonurine and leonurine combined with cisplatin was examined in C33A and Ms751 cells. The cell counting kit-8 assay and bromodeoxyuridine assay were applied for measuring cell proliferation. CompuSyn software was used to calculate the combination index and assess the synergistic effect of leonurine and cisplatin on cell proliferation. The cell cycle distribution and cell apoptosis were analyzed by flow cytometry. The expression of cleaved caspase-3, poly ADP-ribose polymerase (PARP), B-cell lymphoma-2 associated X (BAX), B-cell lymphoma-2 (BCL-2), P glycoprotein (P-Gp) protein and multiple drug resistance protein 1 (MRP1) was analyzed by Western blotting. Results: Leonurine had time-and dose-dependent anti-proliferative effects on C33A and MS751 cells. Leonurine and cisplatin combination was more efficacious in inhibiting the growth of cervical cancer cells than either of the two drugs. The combined application has shown that the cervical cancer cells were arrested at G1 phase after treatments. Moreover, flow cytometry analysis indicated that the combined treatment could cause more cell apoptosis than the single drug treatment. Consistently, combined treatment elevated BAX/BCL-2 ratio, and the expression of BAX, PARP and cleaved caspase-3 proteins. Mechanistic investigations uncovered that the tumor-inhibiting effects of the co-treatment were mediated by repressing MDR, including MRP1 and P-Gp protein, thereby enhancing the efficiency of cisplatin. Conclusion: Leonurine and cisplatin have synergistic antitumorigenic effects on cervical cancer. Combination with leonurine may serve as a novel strategy for enhancing cisplatin sensitivity via the inhibition of the expression of MRP1 and P-Gp.

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Section: Discussionmentioning

confidence: 99%

Leonurine Promotes Cisplatin Sensitivity in Human Cervical Cancer Cells Through Increasing Apoptosis and Inhibiting Drug-Resistant Proteins

Lin

Pan

et al. 2020

DDDT

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“…The cells were propagated in DMEM and supplemented with 10% heat-inactivated FBS (Hyclone), 10 μg/mL of insulin (Manufacturer, Sigma, St. Louis, MO, USA), and 1% penicillin-streptomycin. MTT assay was utilized to examine the in vitro anti-proliferative activity of the newly prepared ureas following the reported procedures [ 26 , 34 , 35 ]. The 50% inhibitory concentration (IC 50 ) was estimated, after 48 and 72 h for MCF-7 cells, from graphic plots of the dose response curve for each conc.…”

Section: Methodsmentioning

confidence: 99%

Pyridine-Ureas as Potential Anticancer Agents: Synthesis and In Vitro Biological Evaluation

et al. 2018

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In our endeavor towards the development of effective anticancer agents, a novel series of pyridine-ureas 8a–n were synthesized. All the newly prepared derivatives were evaluated in vitro for their growth inhibitory activity towards the proliferation of breast cancer MCF-7 cell line. Compounds 8e and 8n were found to be the most active congeners against MCF-7 cells (IC50 = 0.22 and 1.88 µM after 48 h treatment; 0.11 and 0.80 µM after 72 h treatment, respectively) with increased activity compared to the reference drug doxorubicin (IC50 = 1.93 µM). Moreover, eight selected pyridines 8b, 8d, 8e, 8i, 8j and 8l–n were evaluated for their in vitro anticancer activity according to the US-NCI protocol. Pyridines 8b and 8e proved to be the most effective anticancer agents in the NCI assay with mean inhibition = 43 and 49%, respectively. Both 8b and 8e exhibited anti-proliferative activity against all tested cancer cell lines from all subpanels growth inhibition (GI for 8b; 12–78%, GI for 8e; 15–91%). Pyridines 8b and 8e were screened in vitro for their inhibitory activity against VEGFR-2. Both compounds inhibited VEGFR-2 at micromolar IC50 values 5.0 ± 1.91 and 3.93 ± 0.73 µM, respectively. The most active pyridines were filtered according to the Lipinski and Veber rules and all of them passed these filters. Finally, several ADME descriptors were predicted for the active pyridines through a theoretical kinetic study.

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“…Antiproliferative activity of compounds (7a-c and 8a,b) was evaluated following the protocol of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) reduction assay, as reported previously. [24][25][26] Molecular Docking…”

Section: In Vitro Antiproliferative Activitymentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of New HDAC1 and HDAC2 Inhibitors Endowed with Ligustrazine as a Novel Cap Moiety

Al-Sanea

Gotina

Mohamed

et al. 2020

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Introduction: Histone deacetylases (HDACs) represent one of the most validated cancer targets. The inhibition of HDACs has been proven to be a successful strategy for the development of novel anticancer candidates. Methods: This work describes design and synthesis of a new set of HDAC inhibitors (7a-c and 8a, b) utilizing ligustrazine as a novel cap moiety, and achieving the pharmacophoric features required to induce the desired inhibition. Results: The newly synthesized derivatives were evaluated for their potential inhibitory activity toward two class I histone deacetylases, namely HDAC1 and HDAC2. The tested ligustrazine-based compounds were more potent toward HDAC2 (IC 50 range: 53.7-205.4 nM) than HDAC1 (IC 50 range: 114.3-2434.7 nM). Furthermore, the antiproliferative activities against two HDAC-expressing cancer cell lines; HT-29 and SH-SY5Y were examined by the MTT assay. Moreover, a molecular docking study of the designed HDAC inhibitors (7a-c and 8a,b) was carried out to investigate their binding pattern within their prospective targets; HDAC1 (PDB-ID: 4BKX) and HDAC2 (PDB-ID: 6G3O). Discussion: Compound 7a was found to be the most potent analog in this study toward HDAC1 and HDAC2 with IC 50 values equal 114.3 and 53.7 nM, respectively. Moreover, it was the most effective counterpart (IC 50 = 1.60 µM), with 4.7-fold enhanced efficiency than reference drug Gefitinib (IC 50 = 7.63 µM) against SH-SY5Y cells. Whereas, compound 8a (IC 50 = 1.96 µM) was the most active member toward HT-29 cells, being 2.5-times more potent than Gefitinib (IC 50 = 4.99 µM). Collectively, these results suggest that 7a merits further optimization and development as an effective new HDACI lead compound.

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Development of novel synthesized phthalazinone-based PARP-1 inhibitors with apoptosis inducing mechanism in lung cancer

Cited by 64 publications

References 40 publications

<p>Leonurine Promotes Cisplatin Sensitivity in Human Cervical Cancer Cells Through Increasing Apoptosis and Inhibiting Drug-Resistant Proteins</p>

<p>Leonurine Promotes Cisplatin Sensitivity in Human Cervical Cancer Cells Through Increasing Apoptosis and Inhibiting Drug-Resistant Proteins</p>

Pyridine-Ureas as Potential Anticancer Agents: Synthesis and In Vitro Biological Evaluation

<p>Design, Synthesis and Biological Evaluation of New HDAC1 and HDAC2 Inhibitors Endowed with Ligustrazine as a Novel Cap Moiety</p>

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