Hossam M. Abdallah

P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review

Graphical abstract

In vitro cytotoxic screening of selected Saudi medicinal plants

Many natural products from plants have been identified to exert anticancer activity. It might be expected to be a challenge to look at the Saudi plants in order to discover new sources for new molecules which may have anticancer activity. The methanolic extracts of forty species of plants traditionally used in Saudi Arabia for the treatment of a variety of diseases were tested in vitro for their potential anticancer activity on different human cancer cell lines. The cytotoxic activity of the methanolic extracts of the tested plants were determined using three human cancer cell lines, namely, breast cancer (MCF7), hepatocellular carcinoma (HEPG2), and cervix cancer (HELA) cells. In addition, human normal melanocyte (HFB4) was used as normal nonmalignant cells. Sulforhodamine B colorimetric assay was used to evaluate the in vitro cytotoxic activity of the different extracts. The growth inhibition of 50% (IC50) for each extract was calculated from the optical density of treated and untreated cells. Doxorubicin, a broad-spectrum anticancer drug, was used as the positive control. Nine plant extracts were chosen for further fractionation based on their activity and availability. Interesting cytotoxic activity was observed for Hypoestes forskaolii, Withania somnifera, Solanum glabratum, Adenium obesum, Pistacia vera oleoresin, Caralluma quadrangula, Eulophia petersii, Phragmanthera austroarabica, and Asparagus officinalis. Other extracts showed poor activity.

Antidiabetic and Antioxidant Activities of Major Flavonoids of Cynanchum acutum L. (Asclepiadaceae) Growing in Egypt

Seven flavonoids were isolated from the butanol fraction of the methanolic extract of the aerial parts of Cynanchum acutum L. (Asclepiadaceae). All of which have been isolated for the first time from the genus Cynanchum. Their structures were established as quercetin 3-O-β-galacturonopyranoside (1), quercetin 7-O-β-glucopyranoside (2), tamarixtin 3-O-β-galacturonopyranoside (3), kaempferol 3-O-β-galacturonopyranoside (4), 8-hydroxyquercetin 3-O-β-galactopyranoside (5), tamarixtin 3-O-α-rhamnopyranoside (6), and tamarixtin 7-O-α-arabinopyranoside (7) on the basis of their chromatographic properties, chemical and spectroscopic data. The major isolated flavonoids 1, 2 and 3 were found to exhibit significant antioxidant and antidiabetic activities (by measuring blood glucose and insulin levels). This is the first report about the antioxidant and antidiabetic activities of compounds 1 - 3.

Effect of the Method of Preparation on the Composition and Cytotoxic Activity of the Essential Oil of Pituranthos tortuosus

The aerial parts of Pituranthos tortuosus (Desf.) Benth and Hook (Apiaceae), growing wild in Egypt, yielded 0.8%, 0.6%, and 1.5% (v/w) of essential oil when prepared by hydrodistillation (HD), simultaneous hydrodistillation-solvent (n-pentane) extraction (Lickens- Nickerson, DE), and conventional volatile solvent extraction (preparation of the “absolute”, SE), respectively. GC-MS analysis showed that the major components in the HD sample were β-myrcene (18.81%), sabinene (18.49%), trans-iso-elemicin (12.90%), and terpinen- 4-ol (8.09%); those predominent in the DE sample were terpinen-4-ol (29.65%), sabinene (7.38%), γ-terpinene (7.27%), and β-myrcene (5.53%); while the prominent ones in the SE sample were terpinen-4-ol (15.40%), dill apiol (7.90%), and allo-ocimene (4E,6Z) (6.00%). The oil prepared in each case was tested for its cytotoxic activity on three human cancer cell lines, i.e. liver cancer cell line (HEPG2), colon cancer cell line (HCT116), and breast cancer cell line (MCF7). The DE sample showed the most potent activity against the three human cancer cell lines (with IC50 values of 1.67, 1.34, and 3.38 μg/ml against the liver, colon, and breast cancer cell lines, respectively). Terpinen-4-ol, sabinene, γ-terpinene, and β-myrcene were isolated from the DE sample and subjected to a similar evaluation of cytotoxic potency; signifi cant activity was observed

Protective effect of Calligonum comosum on haloperidol-induced oxidative stress in rat

The aqueous and methanolic extracts of Calligonum comosum were investigated for their antioxidant and dopaminergic effects on haloperidol (HL)-induced neuro- and hepatotoxicities in male albino rat model. The total phenolics, flavonoid content and free radical-scavenging activity of the extracts were determined. The results showed that the antioxidant activity of the methanolic extract was higher than the aqueous one. HL significantly reduced GSH and increased MDA in brain and liver tissues. These values were nearly normalized, in the examined tissues, on concomitant administration of C. comosum methanolic extract with HL. Superoxide dismutase activity in the examined tissues was significantly decreased by HL administration that was normalized by the coadministration of the methanolic extract and, to a less extent, the water extract. Determination of the brain neurotransmitter contents revealed a marked decrease in norepinephrine, dopamine and serotonin, which were restored to near control values by concomitant administration of both C. comosum extracts with HL. The results of this study showed that C. comosum methanolic and aqueous extracts ameliorated HL-induced neuro- and hepatotoxicities in rats.

Isolation of antiosteoporotic compounds from seeds of Sophora japonica.

Chemical investigation of Sophora japonica seeds resulted in the isolation of seven metabolites identified as: genistin (1), sophoricoside (2), sophorabioside (3), sophoraflavonoloside (4), genistein 7,4’-di-O-β-D-glucopyransoide (5), kaempferol 3-O-α–L-rhamnopyranosyl(1→6)β-D-glucopyranosyl(1→2)β-D-glucopyranoside (6) and rutin (7). Compounds 1, 2 and 5 showed significant estrogenic proliferative effect in MCF-7 cell in sub-cytotoxic concentration range. Compounds 1 and 2 showed minimal cell membrane damaging effect using LDH leakage assay. Accordingly, compound 2 (sophoricoside, (SPH)) was selected for further in-vivo studies as a potential anti-osteoporosis agent. The anti-osteoporotic effect of SPH was assessed in ovarectomized (OVX) rats after oral administration (15 mg/kg and 30 mg/kg) for 45 days compared to estradiol (10 µg/kg) as a positive control. Only in a dose of 30 mg/kg, SPH regained the original mechanical bone hardness compared to normal non-osteoporotic group. However, SPH (15 mg/kg) significantly increased the level of alkaline phosphatase (ALP) to normal level. Treatment with SPH (30 mg/kg) increased the level of ALP to be higher than normal group. SPH (15 mg/kg) did not significantly increase the serum level of osteocalcin (OC) compared to OVX group. On the other hand, treatment with SPH (30 mg/kg) significantly increased the level of OC to 78% higher than normal non-ovarectomized animals group. In addition, SPH (15 mg/kg) decreased the bone resorption marker, acid phosphatase (ACP) to normal level and SPH (30 mg/kg) further diminished the level of serum ACP. Histopathologically, sophoricoside ameliorated the ovarectomy induced osteoporosis in a dose dependent manner. The drug showed thicker bony trabeculae, more osteoid, and more osteoblastic rimming compared to OVX group.

Antihyperglycemic activity of Caralluma tuberculata in streptozotocin-induced diabetic rats.

The current study aimed at evaluating the potential and mechanisms of the antidiabetic activity of the methanolic extract (ME) of Caralluma tuberculata as well as its chloroform (CF), n-butanol (BF) and the remaining water fractions (RFs) in streptozotocin-induced diabetic rats. The antidiabetic activity was evaluated through assessing fasting blood glucose (FBG), insulin levels, oral glucose tolerance test (OGTT), glucose utilization by isolated rat psoas muscle, gut glucose absorption and G-6-Pase activity in isolated rat liver microsomes. Both ME and RF showed the highest potency, where ME had superior activity. The mechanism underlying the observed antihyperglycemic activity of ME could be attributed, at least in part, to enhanced skeletal muscle utilization of glucose, inhibition of hepatic gluconeogenesis and stimulation of insulin secretion. ME was standardized through LC-MS analysis for its major pregnanes.

New xanthones and cytotoxic constituents from Garcinia mangostana fruit hulls against human hepatocellular, breast, and colorectal cancer cell lines

ETHNOPHARMACOLOGICAL RELEVANCE Cancer has proceeded to surpass one of the most chronic illnesses to be the major cause of mortality in both the developing and developed world. Garcinia mangostana L. (mangosteen, family Guttiferae) known as the queen of fruits, is one of the most popular tropical fruits. It is cultivated in Southeast Asian countries: Malaysia, Indonesia, Sri Lanka, Burma, Thailand, and Philippines. Traditionally, numerous parts of G. mangostana have been utilized to treat various ailments such as abdominal pain, haemorrhoids, food allergies, arthritis, leucorrhoea, gonorrhea, diarrhea, dysentery, wound infection, suppuration, and chronic ulcer. AIM OF STUDY Although anticancer activity has been reported for the plant, the goal of the study was designed to isolate and characterize the active metabolites from G. mangostana and measure their cytotoxic properties. In this research, the mechanism of antiproliferative/cytotoxic effects of the tested compounds was investigated. MATERIALS AND METHODS The CHCl3 fraction of the air-dried fruit hulls was repeatedly chromatographed on SiO2, RP18, Diaion HP-20, and polyamide columns to furnish fourteen compounds. The structures of these metabolites were proven by UV, IR, 1D, and 2D NMR measurements and HRESIMS. Additionally, the cytotoxic potential of all compounds was assessed against MCF-7, HCT-116, and HepG2 cell lines using SRB-U assay. Antiproliferative and cell cycle interference effects of potentially potent compounds were tested using DNA content flow cytometry. The mechanism of cell death induction was also studied using annexin-V/PI differential staining coupled with flow cytometry. RESULTS The CHCl3 soluble fraction afforded two new xanthones: mangostanaxanthones V (1) and VI (2), along with twelve known compounds: mangostanaxanthone IV (3), β-mangostin (4), garcinone E (5), α-mangostin (6), nor-mangostin (7), garcimangosone D (8), aromadendrin-8-C-β-D-glucopyranoside (9), 1,2,4,5-tetrahydroxybenzene (10), 2,4,3`-trihydroxybenzophenone-6-O-β-glucopyranoside (11), maclurin-6-O-β-D-glucopyranoside (rhodanthenone) (12), epicatechin (13), and 2,4,6,3`,5`-pentahydroxybenzophenone (14). Only compound 5 showed considerable antiproliferative/cytotoxic effects with IC50s ranging from 15.8 to 16.7µM. Compounds 3, 4, and 6 showed moderate to weak cytotoxic effects (IC50s ranged from 45.7 to 116.4µM). Using DNA content flow cytometry, it was found that only 5 induced significant cell cycle arrest at G0/G1-phase which is indicative of its antiproliferative properties. Additionally, by using annexin V-FITC/PI differential staining, 5 induced cells killing effect via the induction of apoptosis and necrosis in both HepG2 and HCT116 cells. Compound 3 produce necrosis and apoptosis only in HCT116 cells. On contrary, 6 induced apoptosis and necrosis in HepG2 cells and moderate necrosis in HCT116 cells. CONCLUSION Fourteen compounds were isolated from chloroform fraction of G. mangostana fruit hulls. Cytotoxic properties exhibited by the isolated xanthones from G. mangostana reinforce the avail of it as a natural cytotoxic agent against various cancers. These evidences could provide relevant bases for the scientific rationale of using G. mangostana in anti-cancer treatment.

Phenolics from Garcinia mangostana Inhibit Advanced Glycation Endproducts Formation: Effect on Amadori Products, Cross-Linked Structures and Protein Thiols

Accumulation of Advanced Glycation Endproducts (AGEs) in body tissues plays a major role in the development of diabetic complications. Here, the inhibitory effect of bioactive metabolites isolated from fruit hulls of Garcinia mangostana on AGE formation was investigated through bio-guided approach using aminoguanidine (AG) as a positive control. Including G. mangostana total methanol extract (GMT) in the reaction mixture of bovine serum albumin (BSA) and glucose or ribose inhibited the fluorescent and non-fluorescent AGEs formation in a dose dependent manner. The bioassay guided fractionation of GMT revealed isolation of four bioactive constituents from the bioactive fraction; which were identified as: garcimangosone D (1), aromadendrin-8-C-glucopyranoside (2), epicatechin (3), and 2,3′,4,5′,6-pentahydroxybenzophenone (4). All the tested compounds significantly inhibited fluorescent and non-fluorescent AGEs formation in a dose dependent manner whereas compound 3 (epicatechin) was found to be the most potent. In search for the level of action, addition of GMT, and compounds 2–4 inhibited fructosamine (Amadori product) and protein aggregation formation in both glucose and ribose. To explore the mechanism of action, it was found that addition of GMT and only compound (3) to reaction mixture increased protein thiol in both glucose and ribose while compounds 1, 2 and 4 only increased thiol in case of ribose. In conclusion, phenolic compounds 1–4 inhibited AGEs formation at the levels of Amadori product and protein aggregation formation through saving protein thiol.

Integracides H-J: New tetracyclic triterpenoids from the endophytic fungus Fusarium sp.

Three new tetracyclic triterpenoids namely, integracides H (1), I (4), and J (5), along with integracides B (3) and F (2) have been isolated from the endophytic fungus Fusarium sp. isolated from the roots of Mentha longifolia L. (Labiatae) growing in Saudi Arabia. The structure elucidation of the isolated compounds was achieved by spectroscopic analysis including UV, IR, 1D ((1)H and (13)C) and 2D ((1)H(1)H COSY, TOCSY, HSQC, HMBC, and NOESY) NMR as well as HRESIMS and comparison with literature data. Integracides H (1) and J (5) showed significant anti-leishmanial activity towards Leishmania donovani with IC50 values of 4.75 and 3.29μM, respectively compared to pentamidine (IC50 6.35μM). Moreover, they displayed potent cytotoxic activity towards BT-549, SKOV-3, and KB cell lines with IC50 values of 1.82, 1.32, and 0.18μM and 2.46, 3.01, and 2.54μM, respectively.