Induction of DNA damage, apoptosis and cell cycle perturbation mediate cytotoxic activity of new 5-aminosalicylate-4-thiazolinone hybrid derivatives

TY - JOUR

T1 - Induction of DNA damage, apoptosis and cell cycle perturbation mediate cytotoxic activity of new 5-aminosalicylate-4-thiazolinone hybrid derivatives

AU - S Ramadan, Wafaa

AU - Saleh, Ekram M

AU - Menon, Varsha

AU - Vazhappilly, Cijo George

AU - Abdu-Allah, Hajjaj H M

AU - El-Shorbagi, Abdel-Nasser A

AU - Mansour, Wael

AU - El-Awady, Raafat

N1 - Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.

PY - 2020/11

Y1 - 2020/11

N2 - Modulation of several targets in cancer cells enhances the effect of anti-cancer drugs. This can be achieved by using combinations of anti-cancer drugs or by designing new drugs with novel pharmacophore structures that target different molecules within cancer cells. We developed a panel of such compounds by accommodating two chemical entities (5-Aminoslicylic acid and thiazolin-4-one) known to have anti-cancer activities into a single framework structure. Using a panel of 7 cancer cell lines, two compounds (HH3 and HH13) showed efficient cytotoxic effects on some types of cancer comparable to the standard anti-cancer drug doxorubicin with tumor specificity and minimal effects on normal fibroblasts. Investigating the molecular mechanisms of the two compounds revealed (i) induction of DNA damage, (ii) cell cycle arrest in G2/M phase and (iii) induction of apoptosis as indicated by annexin-V staining and activation of caspases. These effects were more prominent in HH compounds-sensitive cells (with IC50 < 0.5μM) than -resistant or normal cells (with IC50 > 1μM). Moreover, both compounds modulate the expression and activity of several factors in the DNA damage response pathway (γ-H2AX, ATM, ATR, CHK1, CHK2), cyclins/cyclin dependent kinases and CDC25 phosphatase. Altogether, our results show that both HH3 and HH13 compounds are good candidates as anti-cancer drug leads for certain types of cancer and worth further detailed investigations of their safety and effectiveness on animal/xenograft models.

AB - Modulation of several targets in cancer cells enhances the effect of anti-cancer drugs. This can be achieved by using combinations of anti-cancer drugs or by designing new drugs with novel pharmacophore structures that target different molecules within cancer cells. We developed a panel of such compounds by accommodating two chemical entities (5-Aminoslicylic acid and thiazolin-4-one) known to have anti-cancer activities into a single framework structure. Using a panel of 7 cancer cell lines, two compounds (HH3 and HH13) showed efficient cytotoxic effects on some types of cancer comparable to the standard anti-cancer drug doxorubicin with tumor specificity and minimal effects on normal fibroblasts. Investigating the molecular mechanisms of the two compounds revealed (i) induction of DNA damage, (ii) cell cycle arrest in G2/M phase and (iii) induction of apoptosis as indicated by annexin-V staining and activation of caspases. These effects were more prominent in HH compounds-sensitive cells (with IC50 < 0.5μM) than -resistant or normal cells (with IC50 > 1μM). Moreover, both compounds modulate the expression and activity of several factors in the DNA damage response pathway (γ-H2AX, ATM, ATR, CHK1, CHK2), cyclins/cyclin dependent kinases and CDC25 phosphatase. Altogether, our results show that both HH3 and HH13 compounds are good candidates as anti-cancer drug leads for certain types of cancer and worth further detailed investigations of their safety and effectiveness on animal/xenograft models.

U2 - 10.1016/j.biopha.2020.110571

DO - 10.1016/j.biopha.2020.110571

M3 - SCORING: Journal article

C2 - 32861966

VL - 131

SP - 110571

JO - BIOMED PHARMACOTHER

JF - BIOMED PHARMACOTHER

SN - 0753-3322

ER -