Cryptophycin 1 binds to tubulin at a site distinct from the colchicine binding site and at a site that may overlap the vinca binding site

Mooberry, Susan L.; Taoka, Christy R.; Busquets, Lizette

doi:10.1016/0304-3835(96)04342-x

Cited by 32 publications

(20 citation statements)

References 16 publications

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“…alkaloids so that it is likely that the cryptophycins interact with the Vinca alkaloid binding domain or at a site that overlaps with the Vinca alkaloid binding domain of tubulin [10,11,[15][16][17][18]. Cryptophycins are also exquisitely potent inducers of bcl-2 phosphorylation [19].…”

Section: Introductionmentioning

confidence: 97%

Cryptophycins: A Novel Class of Potent Antimitotic Antitumor Depsipeptides

Shih¹,

Teicher²

2001

CPD

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The antitumor cryptophycins are synthetic derivatives of the desipeptide cryptophycins isolated from the cyanobacterium Nostoc sp. Cryptophycin 52 that is currently in clinical trial in solid tumors, is prepared by total synthesis of four key fragments that are coupled to form the final product. The mechanism of anticancer activity of the cryptophycins has been associated with their destabilization of microtubules and with their induction of bcl-2 phosphorylation leading to apoptosis. The cryptophycins maintain activity against ovarian and breast carcinoma cells that overexpress the multidrug resistance efflux pump P-glycoprotein. Cryptophycin 52 has demonstrated a broad range of antitumor activity against both murine and human tumors. In the human MX-1 breast carcinoma xenograft cryptophycin 55 produced greater-than- additive tumor response in combination with 5-fluorouracil. In human non-small cell lung carcinoma and human small cell carcinoma xenografts, administration of the cryptophycins along with gemcitabine, cisplatin or carboplatin resulted in antitumor activity greater than either agent alone. The cryptophycins appear to be additive with fractionated radiation therapy in the human H460 non-small cell lung carcinoma. In the human HCT116 colon carcinoma, the cryptophycins resulted in a greater than additive tumor response when administered sequentially with 5-fluorouracil or irinotecan. Treatment of animals bearing intraperitoneal human OVCAR-2 ovarian carcinoma with cryptophycin 52 resulted in survival times that were greater than those achieved with docetaxel or paclitaxel. Cryptophycin 52 is currently in early clinical testing.

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Section: Introductionmentioning

confidence: 97%

Cryptophycins: A Novel Class of Potent Antimitotic Antitumor Depsipeptides

Shih¹,

Teicher²

2001

CPD

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“…Antimitotic agents that can deplete cellular microtubules have been classified into 2 major binding sites: vinblastine site and colchicine site (Hamel, 1990;Ludueña et al, 1995). Tubulin binding study using 3 H-CP-52 showed that vinblastine, but not taxol, can effectively inhibit the binding of 3 H-CP-52 to isolated tubulin (Table II), suggesting that CP-52 binds to a region near or identical to the vinca domain (Kerksiek et al, 1995;Mooberry et al, 1996). Our findings are in agreement with those reported previously by other investigators (Smith and Zhang, 1996) who showed that CP-1 inhibited the binding of 3 H-vinblastine, but not colchicine, to 1 H-125 (1.5 ϫ 10 5 /tube) and THP-1 (2.5 ϫ 10 5 /tube) cells were treated with various doses of unlabeled agents as indicated and 3 H-CP-52 (10 ng/tube) in 0.5 ml PBS without FCS for 20 min at 23°C.…”

Section: Discussionmentioning

confidence: 97%

Cellular uptake of a novel cytotoxic agent, cryptophycin-52, by human THP-1 leukemia cells and H-125 lung tumor cells

1998

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Cryptophycin (CP) is a newly developed anticancer agent isolated from the terrestrial cyanobacteria of the genus Nostoc. CP is a mitotic inhibitor, causing cells to accumulate in mitosis with the disappearance of intracellular microtubules. In this report, we studied the interaction and uptake of a new synthetic CP analog, CP‐52, with 2 human tumor cell lines, THP‐1 and H‐125. In vitro colony‐forming assay showed that CP‐52 has antiproliferative activity against THP‐1 and H‐125 cell lines with IC50 of 0.1 ng/ml and 20 μg/ml, respectively; i.e., THP‐1 cells are 200,000 times more sensitive to CP‐52 than H‐125 cells. The uptake of CP‐52 by the target cells was carried out using tritiated CP‐52 (3H‐CP‐52). The uptake of 3H‐CP‐52 by both THP‐1 and H‐125 cells was rapid, reaching a maximum within 20 min. Dissociation experiments showed that CP‐52 interacts with the target cells irreversibly, presumably by binding to specific cellular sites with high affinity. With increasing doses of 3H‐CP‐52, the uptake was found to be saturable, reaching a steady state as the concentrations of 3H‐CP‐52 were raised to about 20 μg/ml. Under this condition, the maximal values of CP‐52 uptake by THP‐1 and H‐125 cells was estimated to be 27 and 136 ng/105 cells, respectively. The uptake and accumulation of 3H‐CP‐52 with the target cells was effectively inhibited by prior treatment with unlabeled CP‐52 and, to a lesser extent, vinblastine and taxol but not adriamycin, colchicine or mitomycin. In addition, the binding of 3H‐CP‐52 to purified tubulin was inhibited by vinblastine but not taxol. This finding suggested that CP‐52 and taxol interact and bind to distinct regions of tubulin molecules. Further, it suggests that, in addition to tubulin, other intracellular and/or membrane components are involved in mediating the binding of CP‐52. Int. J. Cancer 77:869–873, 1998.© 1998 Wiley‐Liss, Inc.

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“…Data suggest that cryptophycin binds within the Vinca alkaloid binding domain of tubulin because cryptophycin inhibited the binding of [ 3 H]vinblastine to tubulin yet did not inhibit the binding of colchicine (Kerksiek et al, 1995;Smith and Zhang, 1996;Bai et al, 1996). The tryptic and chymotryptic cleavage of tubulin in the presence of cryptophycin 1 was consistent with occupation of the Vinca binding site and distinct from occupation of the colchicine binding site (Mooberry et al, 1996). In other respects cryptophycin differs from the Vinca alkaloids.…”

mentioning

confidence: 79%

“…Cryptophycin 1 was originally isolated from cyanobacteria of the genus Nostoc (Schwartz et al, 1990) and is a potent inhibitor of cell proliferation; like the Vinca alkaloids, it causes the specific loss of cellular microtubules (Smith et al, 1994). The direct interaction of cryptophycin 1 and tubulin has been demonstrated (Kerksiek et al, 1995;Mooberry et al, 1996;Smith and Zhang, 1996;Bai et al, 1996). Data suggest that cryptophycin binds within the Vinca alkaloid binding domain of tubulin because cryptophycin inhibited the binding of [ 3 H]vinblastine to tubulin yet did not inhibit the binding of colchicine (Kerksiek et al, 1995;Smith and Zhang, 1996;Bai et al, 1996).…”

mentioning

confidence: 99%