This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Linder, S. Articles by Gupta, R. S. Search for Related Content PubMed PubMed Citation Articles by Linder, S. Articles by Gupta, R. S. Related Collections Related Article

Picropodophyllotoxin or Podophyllotoxin Does Not Induce Cell Death via Insulin-like Growth Factor-I Receptor

Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden

Radhey S. Gupta

Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

To the Editor:

The cyclolignan picropodophyllotoxin (PPP) was recently launched as an anticancer drug specifically targeting insulin-like growth factor-I receptor (IGF-IR; ref. 1). PPP is an epimer of podophyllotoxin (PPT), an established inhibitor of microtubule assembly used to treat genital warts. PPT binds to the colchicine binding site of tubulin (2). PPT-resistant cells are cross-resistant to colchicine, colcemid, and vinblastine (3). PPP is 20- to 50-fold less potent than PPT in inhibition of microtubule assembly (4) and the GI₅₀ of PPP is 50-fold that of PPT (500 versus 10 nmol/L). This would be expected if growth inhibition by PPP is due to microtubule inhibition (discussed in ref. 3). Also consistent with this notion is that PPT-resistant cells are resistant to PPP (3).

Despite the documented microtubule effects, an association between IGF-IR expression and sensitivity to PPT/PPP was reported (1). Eleven cell types expressing IGF-IR were found sensitive to PPP, and three cell types lacking IGF-IR expression were resistant in vitro and/or in vivo (1). The in vitro GI₅₀ for cell types lacking IGF-IR expression (R– cells, HepG2 cells) was >15 µmol/L for both drugs (1).

S. Linder and M. C. Shoshan reexamined PPT/PPP effects on IGF-IR–deficient R– cells, which were reported resistant to 15 µmol/L PPT/PPP (1). R– cells (from Dr. Renato Baserga, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA) and mouse embryo fibroblasts (MEFs) were exposed to 0.5 µmol/L PPT or PPP (from Dr. Girnita, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden), a concentration used to inhibit IGF-IR (5). Both cell types were equally sensitive; PPP reduced viability of R1– cells to 52.6 ± 7.5% of control and of MEFs to 58.3 ± 6.4% of control, whereas PPT reduced viability to 51.8 ± 2.2% and 58.3 ± 6.4% of control, respectively [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; 40 h]. Four independent experiments yielded similar results. Both drugs induced sub-G₁ debris in R– cells, indicative of cell death (PPT, 64% of total counts; PPP, 56%; controls, 6%).

PPP induces G₂-M arrest (5). This effect is not dependent on IGF-IR: PPP (0.5 µmol/L, 12 h) induced G₂-M arrest in IGF-1R–deficient cells (43.5% in G₂-M; 24.8% in untreated cells).

R. S. Gupta reexamined PPT/PPP effects on HepG2 cells, which were reported resistant to >15 µmol/L PPT/PPP (1). HepG2 cells were sensitive to PPT and PPP; the IC₉₀ was 30 nmol/L for PPT and 0.5 µmol/L for PPP.

PPT treatment of cancer is limited by severe side effects. Although IGF-IR is an attractive cancer therapy target, our data showing that PPT and PPP induce loss of viability and cell death in IGF-IR–deficient cells contest their potential as IGF-IR–specific anticancer drugs.

References

1. Girnita A, Girnita L, del Prete F, Bartolazzi A, Larsson O, Axelson M. Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth. Cancer Res 2004;64:236–42.[Abstract/Free Full Text]
2. Cortese F, Bhattacharyya B, Wolff J. Podophyllotoxin as a probe for the colchicine binding site of tubulin. J Biol Chem 1977;252:1134–40.[Abstract/Free Full Text]
3. Gupta RS. Podophyllotoxin-resistant mutants of Chinese hamster ovary cells: cross-resistance studies with various microtubule inhibitors and podophyllotoxin analogues. Cancer Res 1983;43:505–12.[Abstract/Free Full Text]
4. Loike JD, Brewer CF, Sternlicht H, Gensler WJ, Horwitz SB. Structure-activity study of the inhibition of microtubule assembly in vitro by podophyllotoxin and its congeners. Cancer Res 1978;38:2688–93.[Abstract/Free Full Text]
5. Strömberg T, Ekman S, Girnita L, et al. IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G₂-M-phase accumulation and apoptosis in multiple myeloma cells. Blood 2006;107:669–78.[Abstract/Free Full Text]

This article has been cited by other articles:

				Editor's Note Cancer Res., July 1, 2007; 67(13): 6529 - 6529. [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Linder, S. Articles by Gupta, R. S. Search for Related Content PubMed PubMed Citation Articles by Linder, S. Articles by Gupta, R. S. Related Collections Related Article