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Revista de la Sociedad Entomológica Argentina

versión impresa ISSN 0373-5680versión On-line ISSN 1851-7471

Rev. Soc. Entomol. Argent. vol.77 no.4 La Plata dic. 2018



Protective effects of Berberís crataegina DC. (Ranunculales: Berberidaceae) extract on Bleomycin-induced toxicity in fruit flies (Diptera: Drosophilidae)


ATICI, Tugba1, ALTUN QOLAK, Deniz2* & ERSOZ, Qagla1

1    Institute of Natural and Applied Science, Erzincan Binali Yildirim University, Erzincan, Turkey.
2    Department of Biology, Faculty of Art and Science, Erzincan Binali Yildirim University, Erzincan, Turkey. * E-mail:

Received 02 - X - 2018 | Accepted 06 - XII - 2018 | Published 27 - XII - 2018

Efectos protectores de extracto de Berberís crataegina DC. (Ranunculales: Berberidaceae) frente a toxicidad inducida con Bleomicina en moscas de la fruta (Diptera: Drosophilidae)

RESUMEN. Los agentes antineoplásicos, debido a sus efectos citotóxicos, aumentan la cantidad de radicales libres en las células causando su muerte. Los objetivos de este estudio fueron evaluar los posibles efectos tóxicos de la Bleomicina (BLM) en el número de descendientes y la tasa de supervivencia de las moscas de la fruta, asi como el papel protector de extractos de frutas de Berberís crataegina DC. (BCE) sobre estos efectos. Las soluciones preparadas en diferentes concentraciones (0,125 mg/ml para BLM; 10 y 20 mg/ml para BCE) se aplicaron a individuos adultos de tipo salvaje de la mosca de la fruta (Drosophila melanogaster) y a larvas de 72 ± 4 h para determinar el número de descendientes y la tasa de supervivencia, respectivamente. Como resultado, el mayor número de descendientes y la tasa de supervivencia en los grupos en los que se aplicaron BCE + BLM que en los grupos tratados solo con BLM muestra que BCE es un antioxidante y tiene un efecto protector (p <0.05). Este efecto protector puede explicarse como una prevención de la formación o bien una eliminación de radicales libres en el ambiente.

PALABRAS CLAVE. Agentes antineoplásicos. Descendencia. DrosophUa melanogaster. Tasa de supervivencia.

ABSTRACT. Antineoplastic agents due to their cytotoxic effects increase the amount of free radical in cells causing cell death. The aims of this study were to assess the possible toxic effects of Bleomycin (BLM) on the number of offspring and survival rate of fruit flies as well as the protective role of Berberis crataegina DC. fruit extracts (BCE) on these effects. Solutions prepared in different concentrations (0.125 mg/mL for BLM; 10 and 20 mg/mL for BCE) were applied to the adult fruit fly Drosophila melanogaster's wild-type individuals and 72 ± 4 h larvae to determine the number of offspring and survival rate, respectively. As a result, the higher number of offspring and survival rate in the BCE + BLM applied groups than the only BLM applied groups shows that BCE is an antioxidant and has a protective effect (p< 0.05). This protective effect can be explained as the prevention or removal of the free radicals formation from the environment.

KEYWORDS. Drosophila melanogaster. Antineoplastic agents. Offspring. Survival rate.



Cáncer is a genetic disorder caused by the alteration of a normal DNA cell due to exposure to physical, Chemicals or biological agents (Van Zanden et al., 2005) . Cancer disease is still one of the most important health problems and cause of death in our world where technology is developing rapidly. Globally, about 7.6 million people lose their lives from cancer each year. By the year 2025, this number is estimated to be about 25 million (Siegel et al., 2014). Recently, alternative methods have been developed in the treatment of cancer, but radiotherapy, chemotherapy, surgery, and immunotherapy have been used in general (Konishi et al., 2003). Today, the most common cancer treatment is chemotherapy. Chemotherapeutic drugs used in the treatment of cancer affect tumor cells and prevent growth and proliferation of cells. On the other hand, these drugs also affect normal cells in the body, leading to various side effects. Chemotherapy drugs known as antineoplastic agents are chemical sources of free radicals (Deavall et al., 2012).

Many studies have shown that chemotherapy drugs cause free radical production both in vivo and in vitro (Sabuncuoglu et al., 2012). Free radicals that form due to metabolic events, nutrients, ultraviolet, radiation, microorganisms, allergens, and cigarette smoke or respiratory effects in the body can easily bind to DNA or cellular proteins, leading to oxidative stresses (Slater, 1988; Grisham & Granger, 1989). This results in severe damage to the cell, tissue, and organs. Dysfunctions that develop together with the damages cause curing of diseases such as cancer, immunologic disorders, diabetes, hypertension, and renal failure (Halliwell, 2006) . Throughout history, people have utilized plants primarily to treat diseases. This bond between man and plant, which has been around for centuries, has been gained by trial and error and has been brought up today (Kendir & Güveng, 2010). There are reports that wild plants used for various purposes contain higher levels of antioxidants and vitamins than cultured plants (Alarcón et al., 2006). Berberís crataegina DC. (Berberidaceae) fruits are known by different names in Turkish such as "karamuk” and "kadin tuzlugu”. All parts of this plant are used worldwide in traditional medicine for the treatment of various diseases (I§ikli & Yilmaz, 2014). Fruits of Berberis sp. are edible and rich in vitamin C and contain a large amount of anthocyanin (Akbulut et al., 2009). Anthocyanins and other phenolic compounds are potent scavengers of free radicals, although they can also behave as pro-oxidants (Konczak & Zhang, 2004). The elemental composition, phenolic compounds and organic acid concentrations of fruits and leaves from B. crataegina (Gulsoy et al., 2011; Kaya et al., 2018Sonmezdag et al., 2018) was determined. Fruits and leaves of B. crataegina were identified with the highest concentrations of phenolics such as chlogenic acid and rutin, and organic acids such as malic acid and citric acid, respectively. Calcium and Potassium are present in high levels in leaves and fruits, respectively (Gulsoy et al., 2011). A previous study revealed that methanolic extract of B. crataegina fruits may be a potent antioxidant nutrient and also may exert a protective role against lipid peroxidation as well as oxidative DNA damage (Charehsaz et al., 2015). Natural antioxidants, which are taken up by various foods, have recently become of interest in the prevention of cancer, as well as the protection from free radical damage, which is caused by toxic agents; studies on this issue are increasing day by day (Gerber et al., 2002). Antioxidants, originated from both endogenous and exogenous sources, can inhibit the damage caused by free radicals (Husain & Kumar, 2012). Chemotherapy drugs are chemical sources of free radicals. It is reported that various categories of cytotoxic agents cause free radical production both in vitro and in vivo (White et al., 2006; Simone et al., 2007; Crohns et al., 2009). Due to chemotherapy in cancer patients, plasma lipid peroxidation products are at a high level and plasma free radical scavenging capacity and plasma antioxidant levels such as vitamins A, E, C are lower, too (Weijl et al., 1997). Chemotherapy-induced reactive oxygen radicals (ROS) can damage macromolecules such as DNA, RNA, protein, and lipid, causing cell death (Brea-Calvo et al., 2006; Crohns et al., 2009). Antioxidant levels of cancer patients have been reported to be important in terms of response to chemotherapy (Seifried et al., 2003, 2007). In vitro studies and animal studies have shown that the application of free radical scavengers together with cytostatic agents such as doxorubicin and cisplatin does not reduce antitumor efficiency and that survival rate in animals treated with antioxidants is higher than that of only chemotherapy treated (Weijl et al., 1997) and also antioxidants did not reduce the antitumoral effect of chemotherapy in clinical trials (Seifried et al., 2007). In another study, vitamins E, A, and C have been used against the oxidative stress related to chemotherapy and radiotherapy. It is observed that vitamins increase the therapeutic efficiency in vivo and in vitro and protect normal cells from apoptosis (Blumenthal et al., 2000).

Bleomycin, used in the treatment of cancer, is an antibiotic derived from    Streptomyces verticillus (Bacteria: Streptomycetaceae) (Kalemci et al., 2014). Bleomycin is seen to be concentrated mostly in the lung and skin. Therefore, these organs are most affected by the side effects of this anticarcinogenic antibiotic. Bleomycin acts by producing ROS such as superoxide and hydroxyl radicals in contrast to other anticancer drugs (Sógüt, 2002). Studies have indicated that the Bleomycin-iron complex formed in cells reduces molecular oxygen to superoxide and hydroxyl radical, creating a break in the DNA chain (Qelikezen & Ertekin, 2009). Also, it has been also reported that antioxidant therapy inhibits DNA and cell damage due to Bleomycin in these studies (Erden et al., 2008). Berberis crataegina and its hybrids are often consumed as food. Berberís species have been used particularly against ¡nflammatory    disorders in worldwide traditionalmedicines (Yetada, 2002). Including alkaloids such as berbamin, berberine, and berberrubine, Berberis has antioxidant, antitumor and antibacterial effects (Melianet al., 2011). In addition, it has been determined that Berberis species are effective bioactive phytochemical sources due to their high content of phenolic compounds and anthocyanins (Yildiz et al., 2014).

From this point of view, in this study, we have investigated the therapeutic roles of B. crataegina, a wild plant used for nutrition and therapeutic purposes, against the possible toxic effects of Bleomycin, one of the antibiotics used in chemotherapy, by survival rate and a number of offspring experiments in the fruit fly DrosophUa melanogaster (Diptera: Drosophilidae).


Experimental animals

We used adult individuals and third instar larvae of the Oregon strain of D. melanogaster DrosophUa is an ideal experimental organism with short life cycles (910 days), large numbers of offspring, low growth time and high human resemblance (Uysal et al., 2009).

Plant and chemicals

Berberis crataegina (100 g) were provided from Tercan/Erzincan province (Turkey) and authenticated by Prof. Dr. Ali Kandemir. Fresh fruits were dried at room temperature. The maceration extraction method was selected in order to obtain fruits extract. Fruits were placed in an Erlenmeyer with absolute ethanol as solvent (1:5 solid/solvent ratio) and left to macerate in the dark for 24 h at room temperature. After the extraction method was completed, the extract solution was allowed to cool. The combined extract was filtered through a Whatman filter. Finally, the sticky residue was dissolved in distilled water and solutions were prepared. 10 and 20 mg/mL concentrations of BCE were used. Bleomycin (CAS number 9041-93-4) were tested as the clinical preparations Platistine® (Pfizer Ltda., Sao Paulo, Brazil). BLM was dissolved in fresh distilled water before use. The experiment concentration of BLM was determined to be 0.125 mg/mL.

Number of offspring determination

Pre-stocked DrosophUa individuals were transferred to medium containing fresh food for collection of virgin female and male individuals of the same age (1-3 days). After 5-6 days, the parents were removed from the environment so that parents and offspring did not interfere. After about 9-10 days, 1-3 days-old virgin female and male individuals were collected in separate media. Five females and five males individuals were used for each application group. Solutions prepared in different concentrations (0.125 mg/mL for BLM; 10 and 20 mg/mL for BCE) were applied to the adult individuals with Standart DrosophUa Medium (SDM) to determine the number of offspring. In all applied groups, in a set of experiment, BLM and BCE applied to the female members (males were fed in only SDM), while in another set of an experiment for the same group, BLM and BCE were applied to male members (females were fed in the only SDM). All culture media were kept at 25 ± 1 °C and 40-60% relative humidity for five days. At the end of the fifth day, exposed individuals and unexposed individuals were mated in SDM. Three days later the parents were distracted from the environment. Following the pupation in the culture media, the adult flies were counted for seven days. The experiments were repeated three times.

Survival rate determination

For survival rate experiments, 1-3 days-old virgin DrosophUa individuals were transferred to fresh media as five females X five males and kept at 25 ± 1 °C and 40-60% relative humidity for three days. At the end of the third day, the parents were removed from the media to collect the larvae. Later, distilled water was placed in a clean petri dish and a piece was taken from the media containing the third instar larvae (72 ± 4 h) to separate the larvae with the distilled water. One hundred larvae were counted for control and application groups. While preparing application groups, to observe the effects of BLM and BCE separately, 2.5 mL of 0.125 mg/ mL BLM and BCE (10 and 20 mg/mL) were pipetted into 25 mL of the culture media and mixed and to determine the healing effects of BCE, 2.5 mL BCE (10 mg/mL and 20 mg/mL) and 2.5 mL BLM were added to the culture media. The larvae of the control group were embedded in the SDM and the mouths of the bottles were covered with cotton plugs and put in an oven. During this process, all experimental groups were checked every day. A number of adult flies were recorded twice a day by making a distinction between male and female. All experiments were conducted in triplicate.

Statistical analysis

Statistical analyses were performed using a computer program (SPSS 15.0 software). One-way analysis of variance (ANOVA) was used to compare the survival rate and the number of offspring of control and treatment groups. p< 0.05 was taken into account in statistical evaluations. Graphs showing survival rate and individual numbers of F1 generations were also drawn using the Microsoft Windows Office-Excel program.


The data obtained as a result of the experiments to examine the effects of BLM and BCE on the number of offspring are shown in Table I and Fig. 1. In female individuals treated with BLM, the number of offspring decreased compared to the control, whereas in the individuals treated with BLM + BCE, the number of offspring approached the control (Table I).

Fig. 1. Effects of Berberís crataegina fruit extracts (BCE) against Bleomycin (BLM) on offspring number of Drosophila melanogaster

Table I. Effects of Berberís crataegina fruit extracts (BCE) against Bleomycin (BLM) on offspring number of Drosophila melanogaster


In the same way, as a result of applying BLM to male individuals, the number of offspring decreased with respect to the control group, whereas in male individuals treated with BLM + BCE, the number of offspring approached the control (Fig. 1). In both groups treated only with BCE, the number of total offspring was higher than control (Fig.1).

The data obtained as a result of the experiments to examine the effects of BLM and BCE on the survival rate are shown in Table II and Fig. 2. According to the results obtained, the survival rate in the larvae treated with BLM decreased compared to the control, while the percentage of survival in the larvae treated with BLM + BCE was close to control (Table II). Also, in the larvae treated only with BCE, the survival rate is higher than control (Fig. 2).

Fig. 2. Effects of Berberís crataegina fruit extracts (BCE) against Bleomycin (BLM) on the survival rate of Drosophila melanogaster    _



Table II. Effects of Berberís crataegina fruit extracts (BCE) against Bleomycin (BLM) on the survival rate of Drosophila melanogaster


The mean survival rate ± standard error









39 ±1.15c



10 BCE


39 ±1.15c


20 BCE

46 ±1.73e



0.125 BLM

17 ±1.15a

13 ±1.73a



As a result of statistical analyses, it was determined that there is a significant difference between control and application groups. These differences observed with respect to control were found to be significant at p< 0.05 level.

Direct results about the effect of Bleomycin and B. crataegina on the development of D. melanogaster have not been found in the literature. Therefore, the results obtained from the study are evaluated in light of the data attained from studies on the effects of related

substances on different organisms in the literature.

A study by Sleijefer (2001) reported that BLM produced reactive oxygen radicals containing superoxide and hydroxyl radicals. Giri et al. (2002) reported that nitric oxide production plays a role in the pathogenesis of pulmonary fibrosis caused by Bleomycin and that aminoguanidine is an important indicator to identify the morphologic and biochemical first stages of the disease and to minimize the effect of Bleomycin. In another study of the oxidative and antioxidant status of plasma and erythrocytes and the protective role of erdosteine and vitamin E in rats given BLM, Bleomycin increased nitric oxide levels, an indicator of oxidative stress (Armutgu et al., 2004). In addition to increasing indirect lipid peroxidation by reducing SOD and GSH activities, BLM also triggers MDA formation in some other ways (Hagiwara et al.2000). Statistically significant increases in the levels of malondialdehyde (lipid peroxidation) were measured in analyses performed on rats with Bleomycin. According to the research, Bleomycin toxicity is associated with lipid peroxidation leading to damage to cellular membranes (Qelikezen & Ertekin, 2009).

In many studies, BLM was used in tissue damage and cell type-specific knockdown models by feeding in young Drosophila flies (Tian & Jiang, 2017; Tian et al., 2017; Xu et al., 2017). In 8,500 cancer patients receiving chemotherapy, multiple nutrient combinations have been shown to reduce side effects without interaction with therapy, prolongation of survival time, and increased treatment response. In 103 children, it is also seen that antioxidant vitamin supplements decreased chemotherapy-induced toxicity and infection risk (Stallings, 2008). In a study conducted with B. crataegina extract, it was reported that in plant extract-treated lymphocytes, DNA damage due to oxidative stress caused by hydrogen peroxide was prevented and plant extracts showed high antioxidant properties (Charehsaz et al., 2015).

It is seen that the results obtained from the research matched with the literature. The toxic effect observed in the BLM-applied group is probably due to the free radicals formed. In addition, we believe that the probable reason for the survival rate and offspring number in the BLM+BCE application groups to be close to the control group is that the plant extracts show strong antioxidant properties.

The present study is the first to investigate Bleomycin and B. crataegina on the development of D. melanogaster. In addition, the use of D. melanogaster as an experimental organism is of special importance because of the high degree of gene similarity with human (Schneider, 2000; Marsh & Thompson, 2006). Because of this gene similarity, the results obtained could increase the degree of applicability in terms of human health.

Since the drugs used in cancer treatment harm cancer cells as well as healthy cells, it is becoming increasingly important to search for alternative drugs that are obtained from natural sources, especially plants, with no side effects. Today, a large number of plants are used medically. For this reason, alternative medicine methods based on plants have emerged (Dwivedi et al., 2011). In this respect, a compilation of useful information about wild plants that have been tested by the public for many years is an important issue (Tulukcu & Sagdig, 2011). Forming a bridge between Asia and Europe, Turkey is home to many plant species as a result of this geographical location. Our country is among the leading countries of the world in terms of plant diversity. However, the number of studies to elucidate the medical properties of our plant species is insufficient. The increase in the study to be carried out in this direction will be again both on behalf of our country and on behalf of cancer studies.


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