Bcl-xL (Ki = 0.5-0.6 μM); Bcl-2 (Ki = 0.2-0.3 mM)

棉酚是一种从棉籽和根中提取的天然物质，已被研究作为一种潜在的抗癌剂。多项临床试验已经检验了外消旋形式的棉酚 [(±)-棉酚]，其耐受性良好。外消旋形式的棉酚 ((±)-Gossypol) 与 Bcl-xL 蛋白结合时的 Ki 为 0.5 至 0.6 μM。此外，(±)-棉酚对 Bcl-2 蛋白具有很强的亲和力，Ki 值为 0.2–0.3 mM。 (-)-棉酚和(+)-棉酚对映体均存在于天然存在的外消旋棉酚中。在 6 天的 MTT 测定中，根据 UM-SCC-6 和 UM-SCC-14A 评估棉酚的外消旋形式及其每种对映体。在两种测试的细胞系中，与(±)-棉酚相比，(-)-棉酚表现出比(+)-棉酚更大的生长抑制作用(P < 0.001)。 (±)-棉酚具有中等生长抑制作用，但仅在较高剂量的棉酚下（10 μM，P<0.0001）[1]。

在 6 天 MTT 细胞存活测定中，将两种代表性 UM-SCC 细胞系 UM-SCC-6 和 UM-SCC-14A 连续暴露于 0、5 或 10 μM 的 (±)-棉酚，(- )-棉酚，或(+)-棉酚[1]。

Absorption, Distribution and Excretion
Lipid-soluble gossypol is readily absorbed from the GI tract. It is highly protein-bound to amino acids, especially lysine, and to dietary iron. Conjugation, metabolism, and urinary excretion of gossypol is limited; most is eliminated in the feces.

Toxicity Summary
Gossypol may cause apoptosis via the regulation of Bax and Bcl-2 proteins. It is also an inhibitor of calcineurin and protein kinases C, and has been shown to bind calmodulin. (L1239)

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Interactions
... Cockerels (n = 144) from lines divergently selected for humoral immunity were used. Three individuals from each line were randomly assigned to a cage and fed a corn-soybean meal (control) diet for 14 d. Six cages per line were then randomly assigned 1 of 4 dietary treatments (1,000 mg/kg of gossypol, 1,000 mg/kg of silymarin, 1,000 mg/kg of both gossypol and silymarin, or a control diet). Body weight and feed intake data were collected for 21 d, with chickens bled weekly to collect plasma and determine hematocrits. Chickens were then killed, and livers were collected for subsequent histology and enzymatic activity analyses. Endpoints measured weekly were analyzed with repeated measures and regression methodologies. Plasma and liver enzyme activities, and histological measures, were analyzed using ANOVA. No significant interactions between diets and lines were observed. Chickens assigned to the gossypol and gossypol-silymarin diets stopped gaining weight at d 14 (P < 0.001) and lost weight by d 21 (P < 0.001). Gamma glutamyltransferase was also elevated in these chickens at d 14; activities increased further by d 21 (P < 0.001). Histological examination of liver slices indicated substantial lipidosis (P < 0.001). Furthermore, quinone reductase activity was higher in gossypol- and gossypol-silymarin-treated chickens than in control and silymarin-treated chickens (P < 0.001). Silymarin did not alleviate any clinical effects of gossypol toxicosis.

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Non-Human Toxicity Values
LD50 Rat oral 2315 mg/kg
LD50 Pig oral 550 mg/kg

[1]. In vitro effects of the BH3 mimetic, (-)-Gossypol, on head and neck squamous cell carcinoma cells. Clin Cancer Res. 2004 Nov 15;10(22):7757-63.

Therapeutic Uses
/Experimental Therapy/ Gossypol (C(30)H(30)O(8)) is a polyphenolic compound derived from the cotton plant (genus Gossypium, family Malvaceae). The presence of six phenolic hydroxyl groups and two aldehydic groups makes gossypol chemically reactive. Gossypol can undergo Schiff base formation, ozonolysis, oxidation, and methylation to form gossypol derivatives. Gossypol and its derivatives have been the target of much research due to their multifaceted biological activities including antifertility, antivirus, anticancer, antioxidant, antitrypanosomal, antimicrobial, and antimalarial activities. Because of restricted rotation of the internaphthyl bond, gossypol is a chiral compound, which has two atropisomers (i.e., (+)- and (-)-gossypol) that exhibit different levels of biological activities.
/Experimental Therapy/ Gossypol, a small molecule inhibitor of pro-survival Bcl-2 family proteins, has been demonstrated to inhibit AI prostate cancer growth. The apoptotic effect of gossypol, however, has been demonstrated to be attenuated by the presence of androgen in a prostate cancer xenograft mouse model (Vertebral Cancer of Prostate [VCaP]) treated with AT-101 (R-(-)-gossypol acetic acid). This study was undertaken to better understand the in vitro effects of androgen receptor (AR) on AT-101-induced apoptosis. VCaP cells treated with AT-101 demonstrated an increase in apoptosis and downregulation of Bcl-2 pro-survival proteins. Upon AR activation in combination with AT-101 treatment, apoptosis is reduced, cell survival increases, and caspase activation is attenuated. Akt and X inhibitor of apoptosis (XIAP) are downregulated in the presence of AT-101, and AR stimulation rescues protein expression. Combination treatment of bicalutamide and AT-101 increases apoptosis by reducing the expression of these pro-survival proteins. These data suggest that combination therapy of AT-101 and ADT may further delay the onset of AI disease, resulting in prolonged progression-free survival of prostate cancer patients. .
/Experimental Therapy/ ... a series of new and known bis-Schiff base analogs of chiral gossypol were synthesized, and their anticancer activity on HeLa, U87 and M85 cells was tested. The results showed that through a simple chemical modification, less active (+)-gossypol could be converted into more active derivatives. When compared with (-)-gossypol, many more potent compounds that could be the promising anticancer agents were found, and some of them were more potent than the anticancer drug Cisplatin against all three cancer cell lines... /Gossypol analogs/
/Experimental Therapy/ Gossypol 10 mg PO bid /was administered in 27 patients with pathologically confirmed glial tumors which had recurred after radiation therapy. Fifteen patients had glioblastoma, 11 patients anaplastic astrocytoma, 1 patient relapsed low grade glioma. Response was assessed every 8 weeks using CT/MRI scan and clinical criteria including decadron requirement. Treatment was continued until disease progression. Two patients had partial response (PR); 4 had stable disease for 8 weeks or more. One patient maintained a PR with improved KPS for 78 weeks. The other had a PR lasting 8 weeks. Toxicity was mild: 2 heavily pretreated patients had mild thrombocytopenia, 5 patients developed hypokalemia, 3 patients developed grade 2 hepatic toxicity and peripheral edema. Gossypol levels measured by HPLC did not correlate with response or toxicity in this study. We conclude that gossypol is well tolerated and has a low, but measurable, response rate in a heavily pretreated, poor-prognosis group of patients with recurrent glioma...
For more Therapeutic Uses (Complete) data for Gossypol (7 total), please visit the HSDB record page.

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Drug Warnings
Following clinical trials conducted in China in the 1970s, gossypol was proposed as a drug for male contraceptive use. This review summarizes the extensive investigations on formal animal toxicology and on the recovery of fertility in men after stopping gossypol treatment which led to the decision by the Special Programme of Research, Development and Research Training in Human Reproduction (HRP) at the World Health Organization (WHO), that gossypol would not be acceptable as an antifertility drug. ... There have been reports that studies conducted in China confirm the efficacy of gossypol as a male antifertility drug. ... Studies conducted by the International Organization for Chemical Sciences in Development showed that 40 of the 70 highly purified, novel structural forms of gossypol were no more active than gossypol. Experiments conducted on Sprague-Dawley rats and cynomolgous monkeys confirm that either (-) or (+) gossypol is too toxic to be developed for human contraception. Among the side effects associated with the use of gossypol, the most serious was hypokalemic paralysis, although differences in reported incidences could be attributed to the regional differences in dietary intake of potassium and genetic predisposition. On the other hand, studies that examine the risk of permanent sterility among healthy reproductive males were confirmed by two separate studies, which found an incidence of 25% irreversible sterility. The failure of recovery among those who stopped gossypol use could be attributed to longer treatment, greater total dose of gossypol, smaller testicular volume, and elevated follicle stimulating hormone concentrations...

C30H30O8

518.5544

518.194

C, 69.49; H, 5.83; O, 24.68

303-45-7

Gossypol (acetic acid);12542-36-8;Gossypol-13C2

3503

Light yellow to yellow solid powder

1.4±0.1 g/cm3

707.9±55.0 °C at 760 mmHg

181-183ºC

395.9±28.0 °C

0.0±2.3 mmHg at 25°C

1.742

6.16

155.52

6

8

5

38

780

0

O([H])C1C2C(C([H])=O)=C(C(=C(C([H])(C([H])([H])[H])C([H])([H])[H])C=2C([H])=C(C([H])([H])[H])C=1C1=C(C2C(C([H])=O)=C(C(=C(C([H])(C([H])([H])[H])C([H])([H])[H])C=2C([H])=C1C([H])([H])[H])O[H])O[H])O[H])O[H])O[H]

QBKSWRVVCFFDOT-UHFFFAOYSA-N

InChI=1S/C30H30O8/c1-11(2)19-15-7-13(5)21(27(35)23(15)17(9-31)25(33)29(19)37)22-14(6)8-16-20(12(3)4)30(38)26(34)18(10-32)24(16)28(22)36/h7-12,33-38H,1-6H3

7-(8-formyl-1,6,7-trihydroxy-3-methyl-5-propan-2-ylnaphthalen-2-yl)-2,3,8-trihydroxy-6-methyl-4-propan-2-ylnaphthalene-1-carbaldehyde

Cottonseed Meal Toxin; Pogosin; Gossypol; BL-193; BL 193; BL193; NSC 624336; NSC 56817

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 本产品在运输和储存过程中需避光。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 33.3~100 mg/mL (64.3~192.9 mM)
Ethanol: 8 mg/mL (~15.4 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.01 mM) (饱和度未知) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80+，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。