The selective effect of NSC 631570 against cancer cells

W. Nowicky, A. Nowicky, B. Nowicky, J. Hodisch, Ukrainian Anticancer Institute, Vienna, Austria

First indications on the selective effect of NSC 631570 on the cancer cells were provided in an early study when different oxygen consumption by normal liver cells and Ehrlich’s tumor ascitic cells after the incubation with NSC 631570 was revealed.

In the tests on the Jurkat lymphoma model, NSC 631570 has been proven to be a strong apoptosis inductor. Profound research showed NSC 631570 brought about the depolarisation of mitochondrial membranes and consequently the activation of caspases.

Ukrain induced apoptosis in a panel of cancer cell lines (cervical cancer HeLa, HeKB, HeKS32, HeBcl3, HeNFR and HeIKK, human colon cancer SW480, human renal carcinoma HEK293, human osteosarcoma MG-63) by activating the caspases of the intrinsic cell death pathway. Interestingly, non-transformed fibroblasts (hTERT) cell line was insensitive to the drug (255). In the tests on human cervix carcinoma cells HeLa, squamous carcinoma cells WHCO5, normal kidney cell line Graham 293, and transformed kidney cell line Vero from African green monkey, NSC 631570 inhibited the tubulin polymerisation and caused a metaphase block in cancer cells which is characterised by abnormal chromosomal distribution, and results in the formation of micronuclei and in apoptosis.

The effects of NSC 631570 on cell survival, alteration of the cell cycle and induction of apoptosis without and in combination with ionising radiation (IR) were investigated on the exponentially growing human tumor cells MDA-MB-231 (breast), PA-TU-8902 (pancreas), CCL-221 (colon), U-138MG (glioblastoma), and human skin and lung fibroblasts HSF1, HSF2 and CCD32-LU. Without IR, NSC 631570 exerted a time- and dose-dependant cytotoxic effect, more pronounced against the cancer cells. The combination of NSC 631570 plus IR enhanced toxicity in CCL-221 and U-138MG cells with their accumulation in the G2/M phase, but not in MDA-MB-231 and PA-TU-8902 cells. A radio protective effect was found in normal human fibroblasts. NSC 631570 caused the accumulation of prostate cancer cells as well as epidermoid carcinoma cells in the G2/M phase, however, not of normal cells.

The cytotoxic effects of NSC 631570 were evaluated in primary pancreatic cancer cell lines (PPTCC), fibroblasts derived from pancreatic ductal adenocarcinoma specimens (F-PDAC), and an immortalized epithelial ductal pancreatic cell line HPNE. Cytotoxic effects of NSC 631570 in PPTCCs were significantly higher than those observed in F-PDAC and HPNE cells. Furthermore, it was revealed that PPTCCs cells consumed more drug than F-PDAC and HPNE cells. This selective effect of Ukrain in PPTCCs may be related to a different transport system or higher metabolism of the drug in PDAC.

Altogether, in comparative studies NSC 631570 has been tested on 18 cancer and 12 benign cell lines at identical conditions so far. In all these experiments the selective effect of NSC 631570 against cancer cells was confirmed. This selective effect of NSC 631570 against cancer cells explains its good tolerability in clinical use.

References.

Roublevskaia IN, Polevoda BV, Ludlow JW, Haake AR. Induced G2/M arrest and apoptosis in human epidermoid carcinoma cell lines by semisynthetic drug Ukrain. Anticancer Res. 2000 Sep-Oct;20(5A):3163-7.

Cordes N, Plasswilm L, Bamber M, Rodemann HP. Ukrain®, an alkaloid thiophosphoric acid derivative of Chelidonium majus L. protects human fibroblasts but not human tumour cells in vitro against ionizing radiation. Int J Radiat Biol 2002, vol. 78, No. 1, 17-27.

Gagliano N, Moscheni C, Torri C, Magnani I, Bertelli A, Nowickz W, Gioia M. Effect of Ukrain on matrix metalloproteinase-2 and Secreted Protein Acidic and Rich in Cysteine (SPARC) expression in human glioblastoma cells. Anti-Cancer Drugs 2006, 17:189-194.