Dual Topoisomerase I / II Inhibitors in Cancer Therapy

Abstract

While the majority of topoisomerase (topo) inhibitors show selectivity against either topo I or topo II, a small class of compounds can act against both enzymes. These can be divided into three classes. The first and largest class comprise drugs that bind to DNA by intercalation and include the clinically-evaluated acridine DACA, the benzopyridoindole intoplicine, the indenoquinolinone TAS-103, the benzophenazine XR11576, and the pyrazoloacridine NSC 366140. The second category comprises hybrid molecules, prepared by physically linking separate inhibitors of topo I and topo II, or by linking pure topo inhibitors to other DNA-interactive carriers. While several derivatives (e.g., camptothecin-epipodophyllotoxin and ellipticine-distamycin hybrids) have been prepared, there have been no detailed studies. The third category are less well defined as a structural class, but apparently recognize structural motifs that are present in both topo I and II enzymes. These include a series of benzoisoquinolinium quaternary salts such as NK 109, and more interestingly modified versions of classical topo I or topo II inhibitors; e.g., the modified camptothecin BN 80927 and the modified epipodophyllotoxin tafluposide (F-11782). There is as yet no detailed understanding of the factors that result in selective or dual inhibition, but structure-activity studies in several classes show that structural changes can influence topo I/II selectivity. DNA intercalation mode also appears to play a part. The basis for the high antitumor activity of some topo inhibitors is not yet understood but may depend on the complex pattern of activities that include both inhibition and poisoning of the two enzymes.

Acridine derivatives activate p53 and induce tumor cell death through bax

“…Their pharmacological properties have been previously evaluated and they have been widely used in the clinic mainly against malaria and some bacterial infections. [22][23][24][25] The anticancer activity of acridine derivatives has also been intensively evaluated. [22][23][24][25] However, the anticancer mechanism of acridine derivatives remains unclear.…”

Bn80927

“…As a dual topoisomerase inhibitor, BN80927 should be compared with other recently reported dual inhibitors of topoisomerase (32) having a dual poisoning mechanism of action, such as Tas-103 (33) or with a catalytic inhibition mode on either Topo I [lucanthone (34)] or both Topo I and II [such as F11782 epipodophyllotoxin derivative (35,36)]. To date, to our knowledge, BN80927 seems to be the only dual inhibitor having both Topo I poisoning and Topo II catalytic inhibitory activities.…”

Structural and Functional Basis for Therapeutic Modulation of p53 Signaling

“…Because Bax(-/-) cells are resistant to acridine derivatives and CP-31398, the mitochondrial pathway must have a role in the mechanism of cell death induced by these compounds. It has also been suggested that acridine derivatives act by intercalating in DNA and subsequently inhibiting topoisomerase I or II, but like CP-31398, these compounds do not act as classic DNA-damaging agents as evidenced by lack of ser15 phosphorylation on p53 (42).…”