BF12, a Novel Benzofuran, Exhibits Antitumor Activity by Inhibiting Microtubules and the PI3K/Akt/mTOR Signaling Pathway in Human Cervical Cancer Cells

Abstract

BF12 [(2E)‐3‐[6‐Methoxy‐2‐(3,4,5‐trimethoxybenzoyl)‐1‐benzofuran‐5‐yl]prop‐2‐enoic acid], a novel derivative of combretastatin A‐4 (CA‐4), was previously found to inhibit tumor cell lines, with a particularly strong inhibitory effect on cervical cancer cells. In this study, we investigated the microtubule polymerization effects and apoptosis signaling mechanism of BF12. BF12 showed a potent efficiency against cervical cancer cells, SiHa and HeLa, with IC50 values of 1.10 and 1.06 μm, respectively. The cellular mechanism studies revealed that BF12 induced G2/M phase arrest and apoptosis in SiHa and HeLa cells, which were associated with alterations in the expression of the cell G2/M cycle checkpoint‐related proteins (cyclin B1 and cdc2) and alterations in the levels of apoptosis‐related proteins (P53, caspase‐3, Bcl‐2, and Bax) of these cells, respectively. Western blot analysis showed that BF12 inhibited the PI3 K/Akt/mTOR signaling pathway and induced apoptosis in human cervical cancer cells. BF12 was identified as a tubulin polymerization inhibitor, evidenced by the effective inhibition of tubulin polymerization and heavily disrupted microtubule networks in living SiHa and HeLa cells. By inhibiting the PI3 K/Akt/mTOR signaling pathway and inducing apoptosis in human cervical cancer cells, BF12 shows promise for use as a microtubule inhibitor.

Anticancer therapeutic potential of benzofuran scaffolds

“…The mechanistic studies showed that benzofuran derivative 12 induced G2/M phase arrest and apoptosis in SiHa and HeLa cells. 40 The in vitro antiproliferative activity of the benzofuran hybrids 13a-h was reported by Dharavath et al against two cell lines; C-6 (nerve cells) and MCF-7 (human breast adenocarcinoma cells) using the MTT method. The bioassay data of the in vitro antiproliferative activity disclosed that the benzofuran derivatives 13b and 13g demonstrated superior inhibition against MCF-7 cell line (with IC 50 1.875 and 1.287 mM, respectively), much better than the cisplatin drug (IC 50 2.184 mM).…”

“…The mechanistic studies showed that benzofuran derivative 12 induced G2/M phase arrest and apoptosis in SiHa and HeLa cells. 40 …”

Cardiovascular protection associated with cilostazol, colchicine and target of rapamycin inhibitors

“…153,155 In vitro studies using cultured human cell lines show that TOR inhibition suppresses tubulin polymerization. 166 Depolymerization of microtubules with colchicine may increase cAMP formation (with a subsequent antifibrotic effect) 167 (Fig. 4).…”

“…Some inhibitors of the PI3K/AKT/ TOR pathway (such as S9 and BF12) inhibit tubulin polymerization by binding to the colchicine domain of tubulin. 166,169 The activity of the PI3K/AKT pathway is upregulated in paclitaxel-resistant prostate cancer cells compared with paclitaxel-responsive prostate cancer cells, suggesting that activity of the PI3K/AKT pathway renders prostate cancer cells resistant to paclitaxel. 170 Interaction Between the Microtubule System and cAMP Signaling Microtubules contribute to regulate adenylyl cyclase activity, so that microtubule disassembly increases the synthesis of cAMP.…”

Investigating the role and mechanism of microRNA‑196a in oral squamous cell carcinoma by targeting FOXO1

“…However, the expression and mechanisms of miR-196a action in OSCCs are not well established. Previous studies have demonstrated that the PI3K/Akt pathway is activated in most types of cancer and suppresses the function of FOXO genes (18)(19)(20)(21)(22). The expression of FOXO1 is upregulated in human OSCCs and is significantly correlated with the advancement of clinical stages (23,24).…”