Ambivalent effects of atorvastatin on angiogenesis, epidermal cell proliferation and tumorgenesis in animal models

A growing body of preclinical data indicates that statins may possess antineoplastic properties; however, some studies have raised the possibility that statins may also have carcinogenic potential. An air pouch model was used for angiogenesis. Single or multiple applications of croton oil on the back of Swiss albino mice with or without initiation by dimethylbenz[a]antheracene [DMBA] were used to evaluate the skin tumorgenesis, ultrastructural and histological alterations. Atorvastatin [orally, 10 mg/kg/day] produced a significant [P<0.05] reduction in angiogenesis. Concurrent administration of mevalonate reversed the antiangiogenic effect of atorvastatin. However, local injection of atorvastatin [200 micro g] into the pouches induced a significant [P<0.5] increase in angiogenesis that was not reversed by co-administration of mevalonate. The disturbance of cell polarity, inflammatory response, thickness of epidermal layer, and mitotic index induced by croton oil were inhibited markedly and dose-dependently [P<0.001] by pre-treatment with atorvastatin. In spite of the strong anti-inflammatory and anti-proliferative effects of atorvastatin on epidermal cell proliferation, it was identified that the same doses of atorvastatin in DMBA-initiated and croton oil-promoted skin tumorgenesis in mice increased the incidence of tumors and their conversion into malignant carcinoma. The reasons for these discrepancies remain unclear, and could be related to ambivalent effects of atorvastatin on angiogenesis or to specific differences in the experimental conditions. It is suggested that the pro-angiogenic effect of the drug, which could be responsible for promotion of skin tumors, is independent of the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibition that can be mediated directly by atorvastatin

Buspirone attenuates tolerance to analgesic effect of morphine in mice with skin cancer

Adjuvant drugs that can delay tolerance to morphine analgesia may lead to improved management of pain in chronic disease such as cancer. This study was aimed to investigate effect of buspirone, as a partial agonist of 5-HT[1A] receptor, on tolerance induced to morphine analgesic effect in animals with skin cancer. Study was carried on female Swiss albino mice. For skin tumorigensis, mice were treated with single dose of 7,12-dimethylbenz [a] anthracene [DMBA] and promoted by multiple dose of croton oil. Tolerance to morphine analgesia was induced by daily subcutaneous [sc] injection of morphine [5mg/kg for 30 days] and assayed by using the hot plate method. Results obtained from this study showed that pain threshold in mice with skin cancer were significantly lower. Tolerance to analgesic effect of morphine [5 mg/kg, sc] was appeared at day 15, whereas, in normal and skin tumor bearing mice co-treated daily with morphine [5 mg/kg, sc] and three different intraperitoneal [ip] doses of buspirone [5, 7.5 and 10 mg/kg] tolerance was observed at days 25 and 30. In conclusion our data indicate that concurrent use of morphine with buspirone may produce good cancer pain control and attenuate development of tolerance

Effect of testosterone on morphine withdrawal syndrome in rats / 亚洲男科学杂志(英文版)

<p><b>AIM</b>To determine whether testosterone is involved in morphine withdrawal syndrome (WS).</p><p><b>METHODS</b>In order to induce dependency, rats were treated with subcutaneous injection of morphine (days 1-2, 5 mg/kg; days 3-5, 7.5 mg/kg; days 6-8, 10 mg/kg), and after the last dose of morphine (day 8) WS was induced by intraperitoneal injection of naloxone (1 mg/kg). Wet dog shake (WDS), abdomen writhing (AW), and jumps (J) were recorded as indicators of WS.</p><p><b>RESULTS</b>The severity of WDS, AW, and J in male rats was greater than that in females. Accordingly, in 4-week castrated and flutamide-treated (10 mg/kg/day for 8 days, i.p.) male rats, WDS, AW, and J were significantly decreased compared to male control rats. Testosterone replacement therapy (10 mg/kg/day for 8 days, i.m.) in 4-week castrated rats restored the severity of WDS, AW, and J behaviors to the level of non-castrated male rats, whereas testosterone potentiated the WDS behavior in non-castrated male rats.</p><p><b>CONCLUSION</b>It can be concluded that testosterone might be effectively involved in morphine WS.</p>

Inhibitory effect of tannic acid from nutgall on iron-dextran augmented 7, 12-dimethyl benz [A] anthracene-initiated and croton oil-promoted skin carcinogenesis

Tannic acid [TA] is naturally occurring polyphenols present in fruits and vegetables. In this study, inhibition of the carcinogenic potential of croton oil in normal and iron overloaded mice skin by TA is reported. Albino Swiss mice were given iron-dextran for two weeks and were pretreated with a single topical application of tannic acid. After one hour tumors were initiated by a single dose of 7,12- dimethylbenz[a]anthracene [DMBA] the promoting agent croton oil was applied twice a week for 30 weeks. The appearance, number and% tumor incidences were recorded. When compared to control groups, the pretreated groups showed a significant high inhibition of tumors incidences. Biochemical studies in mice skin tissues were based on the measurement of lipid peroxidation [LPO]. TA diminished cutaneous LPO level in mice skin as compared to the untreated groups. This study showed that TA inhibits the augmentation potentials of croton oil and iron dextran significantly. A depletion in LPO levels in TA pretreated groups indicates that excessive generated oxidants in the mice skin tissues may be quenched by TA because of chelation of redox active iron and its faster elimination from the body. It is supposed that inhibition of iron mediated oxidative stress by TA may be responsible for diminishment of cutaneous tumorigenesis

Effect of iron overload on 7, 12-dimethyl-benz [A] anthracene-induced skin tumorigenesis

Iron overload is known to occur in the West European and American population due to the consumption of iron-rich diets. On the other hand, genetic disorders leading to iron overload are also known. Iron overload leads to increased peroxidation and disruptive disintegration of lipid-rich membranes, and predisposes humans for an enhanced risk of cancer induction. In experimental animals iron overload enhances intestinal, colonic, hepatic, pulmonary and mammary carcinogenesis. In this study, we have shown that iron overload is a mild tumor promotor in mouse skin. Female albino Swiss mice were iron overloaded and their backs were shaved. Tumors were initiated using a complete tumorigenesis protocol by applying 200[micro]g 7, 12-dimethylbenz [a] anthracene [DMBA]/mouse in multiple doses of 40[micro]g DMBA/day for 5 consecutive days. The appearance of the first tumor [latency period],% of tumor incidence and number of tumors/ mouse were recorded. When compared to the positive control group, the iron overloaded mice showed an increased incidence of tumors. In iron overloaded animals, the tumors appeared about four weeks earlier. The number of tumors per mouse were significantly higher in the iron overloaded group. Biochemical studies performed in the present study include the determination of the activity of lipid peroxidation, catalase and xanthine oxidase measurement in mice skin tissue. We observed an iron-mediated induction in lipid peroxidation [LPO] and xanthine oxidase [XOD] and diminished catalase [CAT] activity in skin tissues of mice overloaded with iron as compared to the normal unloaded control group. Based on these studies we propose that iron increases tumor promotion potentials significantly. An induction in LPO in the iron overloaded group suggests that oxidative stress may be responsible for such an observed augmentation of cutaneous carcinogenesis in mice. Our data indicate that iron overload exerts tumor promoting potential in mouse skin, and that oxidative stress generated by iron overload is responsible for the augmentation of cutaneous tumorigenesis