Biological Activity of N-Hydroxyethyl-4-aza-2,3-didehydropodophyllotoxin Derivatives upon Colorectal Adenocarcinoma Cells

Abstract

Etoposide is a chemotherapy drug derived from the natural lignin podophyllotoxin. Our novel generated Aza-podophyllotoxin compounds (AZP 8a & AZP 9a) are analogues of podophyllotoxin and were previously screened for anti-cancer activity through the NCI 60 cell line screening panel showing activity on various cell types including colon cancer. This study expands the toxicological screening by studying apoptosis and various hallmark events as part of the mechanism of action of these compounds on colon cancer cells. The COLO 205 cell line was selected and exposed to AZP to determine the IC50 doses at 24 hours treatment. Apoptosis hallmark events such as migration of phosphatidylserine (PS) to the cell membrane, DNA fragmentation, cell cycle effects, mitochondrial membrane permeabilization and caspase activation were included. Experiments were performed in triplicates for all tested compounds including AZP 8a, AZP 9a, camptothecin as positive control and vehicle as negative control. Our results present contrasting apoptotic activity between the experimental compounds. Compound 8a presented migration of PS (annexin V assay), DNA fragmentation and cell cycle arrest at S phase. Compound 9a presented PS migration with fragmented DNA, cell cycle arrest at S phase, mitochondrial membrane permeabilization and activation of caspase 3, 8 and 9. Compound 8a without the oxygen atoms in ring A appears to cause effects similarly to autophagy as induced by etoposide, a cancer drug analogue of our heterocyclic compounds. Compound 9a with the oxygen atoms in expanded ring A presented induction of cell death following activation of a classical apoptosis pathway. Our results suggest that minor structural differences among these AZP can account for the difference in biological response and cancer cell toxicity.

In Vivo and in Vitro Antileishmanial Effects of Methanolic Extract From Bark of Bursera Aptera

“…For example, the presence of dead cells by apoptosis and necrosis may be due to the compounds found in the extract, such as podophyllotoxin. This compound registered a greater abundance in the GC-MS. We found that the extract promotes the externalization of phosphatidylserine and a loss of mitochondrial membrane potential, these events are characteristic during programmed cell death (PCD) (Mehta and Shaha, 2004;Sen et al, 2007), and these findings are consistent with those reported by Velez et al (2014), who reported that podophyllotoxin and its analogues have the ability to generate apoptosis in COLO-205 cells to promote the externalization of phosphatidylserine between 20 % and 50 %. This generates permeability of the mitochondrial membrane.…”

Immune Stimulating Outcome of Chrysin and γ-Irradiation via Apoptotic Activation Against Solid Ehrlich Carcinoma Bearing Mice

“…Some previous studies proposed that hydroxyethyl derivatives exhibited stronger anticancer activity. 59,60 Further, the results of histological examination for the tumor micrograph of EAC + Ch and EAC + Ch + R mice groups compared to EAC mice reveals noticeable amelioration in cell architecture of the muscle bundle in addition to certain improvement in the state of tumor cell infiltration, penetration and area of necrosis, and enhancing tumor cells apoptosis (Figure 7). The results give the impression that Ch plays an efficient role in the inhibition of the TNF-α and IFN-γ activation event.…”

Novel Azapodophyllotoxin Induces DNA Cleavage via Groove Binding: An Advancement in Exploration of Anticancer Activity of a Known Inhibitor of Tubulin Polymerization and Topoisomerase

“…With this aim, a new class of potential antitumor agents, azapodophyllotoxins (AZPs), that are nitrogen derivatives of podophyllotoxin have been designed and synthesized [3–7] . Interestingly, these AZPs were highly effective for wide spectrum of cancers as studied so far [8–11] …”

“…[3][4][5][6][7] Interestingly, these AZPs were highly effective for wide spectrum of cancers as studied so far. [8][9][10][11] In the present study, a fascinating AZP derivative, 5-(2-Hydroxyethyl)-9-(3,4,5-trimethoxyphenyl)-6,9-dihydro- [1,3]dioxolo [4,5-g]furo [3,4-b] quinolin-8(5H)-one (HTDQ), (Figure 1) has been investigated that exhibits excellent anticancer activities with GI50 values of less than 1 μM for most of the cancer cell lines. [12] The remarkable properties of these AZPs have beckoned exploration of its mechanism of action.…”