Mechanisms of Action of the Novel Sulfonamide Anticancer Agent E7070 on Cell Cycle Progression in Human Non-Small Cell Lung Cancer Cells

Abstract

E7070 is a novel sulfonamide antitumor agent that exhibits potent antitumor activity in vitro and in vivo. This compound affects cell cycle progression in human tumor cells. To elucidate the mechanisms by which E7070 inhibits tumor cell growth, we established and characterized an E7070-resistant subline, A549/ER, from a human non-small cell lung cancer cell line A549. Flow cytometric analyses demonstrated an increase in G0/G1 and a decrease in S phase populations in cells treated with E7070 at 20 or 100 microg/ml for 24 h. Longer exposure to E7070, i.e. 48 and 72 h, increased the G2/M phase fraction in A549 cells. These inhibitory actions of E7070 on cell cycle progression were not observed in A549/ER cells. E7070 inhibited the phosphorylation of pRb, decreased expressions of cyclin A, B1, CDK2, and CDC2 proteins, and suppressed CDK2 catalytic activity with the induction of p53 and p21 proteins in A549 cells but not in A549/ER cells. Taken together, these results suggest that E7070 exerts its antitumor effects by disturbing the cell cycle at multiple points, including both the G1/S and the G2/M transition, in human lung cancer cells.

Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX

“…In HCT116, one of the most sensitive cancer cell lines, 1 was found to suppress the expression of cyclin E and the phosphorylation of CDK2, both of which are essential for the G1 to S transition. 8 A more detailed mechanistic study by Fukuoka et al 15 clarified that 1 disrupted cellcycle progression at multiple points, including both G1/ S and G2/M transitions, in a human non-small cell lung cancer cell line A549. In their experiments using A549 and its 1-resistant subline A549/ER, the compound was shown to inhibit pRb phosphorylation, to reduce the protein expression of cyclin A, cyclin B1, CDK2 and CDC2, and to suppress CDK2 catalytic activity with the induction of p53 and p21 proteins only in parental (drug sensitive) A549 cells.…”

Drugs That Inhibit Signaling Pathways for Tumor Cell Growth and Proliferation

“…143 Indisulam is also a potent carbonic anhydrase IX inhibitor (for the relevance of this enzyme in cancer, see Section 6 of Chapter 14). This compound decreases the expression of several cell cycle proteins (cyclins A and B1, CDK2, and CDC2) and also suppresses the CDK2 catalytic activity with induction of p53 and p21 proteins in lung cancer cells, disturbing the cell cycle at multiple points including both the Binding of seleciclib to CDK2.…”

Anticancer Potential of N‐Sulfonyl Noscapinoids: Synthesis and Evaluation

“…Agents such as E7010, E7070 are few illustrative examples with anti‐tubulin activity and are relatable to the present work. The sulfonamide moiety not only adds to the stability and crystallinity to the attached heterocyclic unit but is easy to install too . In view of the above‐mentioned knowledge about sulfonamide derivatives I–IX and in continuation of our research program on developing novel noscapine based anticancer agents, herein we describe the rational design and synthesis of new N‐sulfonyl noscapinoids 6 a – n .…”