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  1. Md Roduan MR, Abd Hamid R, Mohtarrudin N
    BMC Complement Altern Med, 2019 Sep 03;19(1):238.
    PMID: 31481122 DOI: 10.1186/s12906-019-2650-1
    BACKGROUND: Annonacin, an annonaceous acetogenin isolated from Annona muricata has been reported to be strongly cytotoxic against various cell lines, in vitro. Nevertheless, its effect against in vivo tumor promoting activity has not been reported yet. Therefore, this study was aimed to investigate antitumor-promoting activity of annonacin via in vivo two-stage mouse skin tumorigenesis model and its molecular pathways involved.

    METHODS: Mice were initiated with single dose of 7,12-dimethylbenz[α]anthracene (DMBA) (390 nmol/100 μL) followed by, in subsequent week, repeated promotion (twice weekly; 22 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA) (1.7 nmol/100 μL). Annonacin (85 nM) and curcumin (10 mg/kg; reference) were, respectively, applied topically to DMBA/TPA-induced mice 30 min before each TPA application for 22 weeks. Upon termination, histopathological examination of skin, liver and kidney as well as genes and proteins expression analysis were conducted to elucidate the potential mechanism of annonacin.

    RESULTS: With comparison to the carcinogen control, Annonacin significantly increased the tumor latency period and reduced the tumor incidence, tumor burden and tumor volume, respectively. In addition, it also suppressed tumorigenesis manifested by significant reduction of hyperkeratosis, dermal papillae and number of keratin pearls on skin tissues. Annonacin also appeared to be non-toxic to liver and kidney. Significant modulation of both AKT, ERK, mTOR, p38, PTEN and Src genes and proteins were also observed in annonacin-targeted signaling pathway(s) against tumorigenesis.

    CONCLUSIONS: Collectively, results of this study indicate that annonacin is a potential therapeutic compound targeting tumor promoting stage in skin tumorigenesis by modulating multiple gene and protein in cancer signaling pathways without apparent toxicity.

    Matched MeSH terms: 9,10-Dimethyl-1,2-benzanthracene/toxicity
  2. Yeong LT, Hamid RA, Yazan LS, Khaza'ai H
    Asian Pac J Cancer Prev, 2013;14(4):2301-5.
    PMID: 23725131
    Ardisia crispa (Family: Myrsinaceae) is an evergreen, fruiting shrub that has been traditionally used as folklore medicine. Despite a scarcity of research publications, we have succeeded in showing suppressive effects on murine skin papillomagenesis. In extension, the present research was aimed at determining the effect of a quinone-rich fraction (QRF) isolated from the same root hexane extract on both initiation and promotion stages of carcinogenesis, at the selected dose of 30 mg/kg. Mice (groups I-IV) were initiated with a single dose of 7,12-dimethylbenz(α)anthracene (DMBA, 100 μg/100 μl) followed by repeated promotion of croton oil (1%) twice weekly for 20 weeks. In addition, group I (anti-initiation) received QRF 7 days before and after DMBA; group II (anti-promotion) received QRF 30 minutes before each croton oil application; group III (anti-initiation/ promotion) was treated with QRF as a combination of group I and II. A further two groups served as vehicle control (group V) and treated control (group VI). As carcinogen control, group IV showed the highest tumor volume (8.79±5.44) and tumor burden (3.60±1.17). Comparatively, group III revealed only 20% of tumor incidence, tumor burden (3.00±1.00) and tumor volume (2.40±1.12), which were significantly different from group IV. Group II also showed significant reduction of tumor volume (3.11), tumor burden (3.00) and tumor incidence (11.11%), along with prominent increase of latency period of tumor formation (week 12). Group I, nonetheless, demonstrated marked increment of tumor incidence by 40% with prompted latency period of tumor formation (week 7). No tumor formation was observed in groups V and VI. This study provided clear evidence of inhibitory effects of QRF during promotion period which was in agreement with our previous findings. The mechanism(s) underlying such effects have yet to be elucidated.
    Matched MeSH terms: 9,10-Dimethyl-1,2-benzanthracene/toxicity
  3. Kadir EA, Sulaiman SA, Yahya NK, Othman NH
    Asian Pac J Cancer Prev, 2013;14(4):2249-54.
    PMID: 23725121
    The study was conducted to determine the effect of Malaysian jungle Tualang Honey (TH) on development of breast cancer induced by the carcinogen 7,12-dimethylbenz(α)anthracene (DMBA) in rats. Forty nulliparous female Sprague-Dawley rats were given 80 mg/kg DMBA then randomly divided into four groups: Group 1 served as a Control while Groups 2, 3 and 4 received 0.2, 1.0 or 2.0 g/kg bodyweight/day of TH, respectively, for 150 days. Results showed that breast cancers in the TH-treated groups had slower size increment and smaller mean tumor size (≤ 2 cm3) compared to Controls (≤ 8 cm3). The number of cancers developing in TH-treated groups was also significantly fewer (P<0.05). Histological grading showed majority of TH-treated group cancers to be of grade 1 and 2 compared to grade 3 in controls. There was an increasing trend of apoptotic index (AI) seen in TH-treated groups with increasing dosage of Tualang Honey, however, the mean AI values of all TH-treated groups were not significantly different from the Control value (p>0.05). In conclusion, Tualang Honey exerted positive modulation effects on DMBA-induced breast cancers in rats in this preliminary study.
    Matched MeSH terms: 9,10-Dimethyl-1,2-benzanthracene/toxicity
  4. Roslida A, Fezah O, Yeong LT
    Asian Pac J Cancer Prev, 2011;12(3):665-9.
    PMID: 21627361
    Ardisia crispa (Family: Myrsinaceae) has been used as a traditional medicine for various ailments. Previous studies showed that Ardisia crispa possesses antimetastatic and anti-inflammatory properties. Nevertheless, research done on the plant is still limited. Therefore, the present study was designed to evaluate the suppression effect of Ardisia crispa root hexane (ACRH) extract on 7, 12-dimethylbenz (α) anthracene (DMBA)-induced mice skin tumor promotion in ICR mice with topical application twice weekly for 10 weeks. Results showed significant difference between treatment groups (mice treated with 30 mg/kg, 100 mg/kg and 300 mg/kg of ACRH extract; denoted as group I, II and III respectively) for tumor incidence and tumor burden (P<0.05). Significant reduction in tumor incidence (20%), tumor burden (1.5 ± 0.50), tumor volume (2.49 ± 1.70) and delayed latency period of tumor formation was observed in group I (30 mg/kg) in comparison to carcinogen control. This study indicates that ACRH extract could be a promising skin tumor promotion suppressing agent at a lower dosage (30 mg/kg). Further studies are required to elucidate the underlying mechanism(s) leading to this effect.
    Matched MeSH terms: 9,10-Dimethyl-1,2-benzanthracene/toxicity
  5. Yeong LT, Abdul Hamid R, Saiful Yazan L, Khaza'ai H, Mohtarrudin N
    BMC Complement Altern Med, 2015;15(1):431.
    PMID: 26638207 DOI: 10.1186/s12906-015-0954-3
    Drastic increment of skin cancer incidence has driven natural product-based chemoprevention as a promising approach in anticancer drug development. Apart from its traditional usages against various ailments, Ardisia crispa (Family: Myrsinaceae) specifically its triterpene-quinone fraction (TQF) which was isolated from the root hexane extract (ACRH) was recently reported to exert antitumor promoting activity in vitro. This study aimed at determining chemopreventive effect of TQF against chemically-induced mouse skin tumorigenesis as well as elucidating its possible pathway(s).
    Matched MeSH terms: 9,10-Dimethyl-1,2-benzanthracene/adverse effects
  6. Rengarajan T, Nandakumar N, Rajendran P, Ganesh MK, Balasubramanian MP, Nishigaki I
    J Physiol Biochem, 2015 Jun;71(2):191-204.
    PMID: 25827943 DOI: 10.1007/s13105-015-0397-9
    Breast cancer is the most prevalent malignant neoplasm in the world, and chemoprevention through dietary intervention strategy is an emerging option to reduce the incidence. D-pinitol (DP), a major component of soya bean, possesses attractive biological actions. We have investigated whether D-pinitol have an effect on tumor growth in vivo against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary carcinogenesis and investigated its mechanism of action. Tumors were induced in Sprague-Dawley (SD) rats by a gastric dose of 20 mg/kg DMBA, and after 13 weeks of induction period, the rats were orally administered with D-pinitol for 45 days. At the end of the assay, animals in carcinogen control group prompted a tumor incidence of 100 % and developed a tumor volume of 8.35 ± 0.56, which was significantly reduced to 5.74 ± 0.32 for the animals treated with D-pinitol. The D-pinitol treatment not only decreased the tumor volume but also further examination revealed that tumors from animals that received D-pinitol reduced nuclear factor kappa B (NF-κB) activation which in turn results in modulation of its downstreaming p53 and proteins of caspase-3 family. Bcl-2 expression and caspase-3 activation were also decreased after D-pinitol supplementation leading to induction of apoptosis and finally cell death. Furthermore, the status of the inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-6, and tumor markers, lipid profile, and hormones was also significantly declined up on D-pinitol administration. Thus, it reveals the collective involvement of the above-mentioned parameters along with NF-κB signaling through which D-pinitol induces apoptosis and subsequently suppresses breast cancer during DMBA-induced rat breast carcinogenesis.
    Matched MeSH terms: 9,10-Dimethyl-1,2-benzanthracene/toxicity
  7. Hawariah A, Stanslas J
    In Vivo, 1998 Jul-Aug;12(4):403-10.
    PMID: 9706492
    Early studies reported that a styrylpyrone derivative (SPD) purified from the Goniothalamus sp. acts as a non-competitive antiestrogen in early pregnant mice (1). In the immature rat uterine wet weight test, we found that SPD markedly reduced uterine weight at doses 1 and 100 mg/kg, thus reflecting negative antiestrogenicity, probably attributed to low binding affinities towards ER. Tamoxifen (Tam) on the other hand exhibited partial antiestrogenicity at all doses (0.01-10 mg/kg BW) and dose-dependent estrogenicity. However, the estrogen antagonism: agonism ratio for SPD is much higher than Tam, which is indicative of the breast cancer antitumor activity as seen in compounds such as MER-25. Pretreatment assessment on 1 mg/kg BW SPD and Tam showed that SPD is not a very good, estrogen antagonist compared to Tam, as it was unable to revert the estrogenicity effect of estradiol benzoate (EB) on immature rat uterine weight. Antitumor activity assessment for SPD exhibited significant tumor growth retardation in 7,12-dimethyl benzanthracene (DMBA) induced rat mammary tumors at all doses employed (2, 10 and 50 mg/kg) compared to the controls (p < 0.01). This compound was found to be more potent than Tam (2 and 10 mg/kg) and displayed greater potency at a dose of 10 mg/kg. It caused complete remission of 33.3% of tumors but failed to prevent onset of new tumors. However, SPD administration at 2 mg/kg caused 16.7% complete remission and partial remission. It also prevented the onset of new tumors throughout the experiment.
    Matched MeSH terms: 9,10-Dimethyl-1,2-benzanthracene
  8. Sundram K, Khor HT, Ong AS, Pathmanathan R
    Cancer Res, 1989 Mar 15;49(6):1447-51.
    PMID: 2493981
    Female Sprague-Dawley rats, 50 days of age, were treated with a single dose of 5 mg of 7,12-dimethylbenz(a)anthracene intragastrically. 3 days after carcinogen treatment, the rats were put on semisynthetic diets containing 20% by weight of corn oil (CO), soybean oil (SBO), crude palm oil (CPO), refined, bleached, deodorized palm oil (RBD PO) and metabisulfite-treated palm oil (MCPO) for 5 months. During the course of experiments, rats fed on different dietary fats had similar rate of growth. Rats fed 20% CO or SBO diet have higher tumor incidence than rats fed on palm oil (PO) diets; however differences of mean tumor latency periods among the groups were not statistically significant. At autopsy, rats fed on high CO or SBO diets had significantly more tumors than rats fed on the three PO diets. Our results showed that high PO diets did not promote chemically induced mammary tumorigenesis in female rats when compared to high CO or SBO diets. CO and SBO differ greatly from the palm oils in their contents of tocopherols, tocotrienols, and carotenes. But further experiments would be required to determine whether the observed differences in tumor incidence and tumor numbers were due to the differences in these minor components or due to the unique triglyceride structure of the palm oils. Analysis of the fatty acid profiles of plasma total lipids of tumor-bearing rats and of the tumor total lipids showed that, with the exception of arachidonic acid, the fatty acid profiles reflect the nature of the dietary fats. At autopsy, there were no differences in the plasma total cholesterol contents among rats fed on different dietary fats, but rats fed on palm oil diets had a significantly higher plasma triglyceride level than that of rats fed CO or SBO diets. As for the tumor lipids, there were no significant differences in the triglyceride, diglyceride, and phospholipid levels when the CO or SBO groups were compared to the palm oil groups.
    Matched MeSH terms: 9,10-Dimethyl-1,2-benzanthracene
  9. Kooi OK, Ling CY, Rodzi R, Othman F, Mohtarrudin N, Suhaili Z, et al.
    PMID: 25392583
    BACKGROUND: Melastoma malabathricum L. Smith (family Melastomaceae) is a shrub that has been used by the Malay practitioners of traditional medicine to treat various types of ailments. The present study aimed to determine the chemopreventive activity of methanol extract of M. malabathricum leaves (MEMM) using the standard 7,12-dimethylbenz(α)anthracene (DMBA)/croton oil-induced mouse skin carcinogenesis model.

    MATERIALS AND METHODS: In the initiation phase, the mice received a single dose of 100µl/100 µg DMBA (group I-V) or 100µl acetone (group VI) topically on the dorsal shaved skin area followed by the promotion phase involving treatment with the respective test solutions (100 µl of acetone, 10 mg/kg curcumin or MEMM (30, 100 and 300mg/kg)) for 30 min followed by the topical application of tumour promoter (100µl croton oil). Tumors were examined weekly and the experiment lasted for 15 weeks.

    RESULTS: MEMM and curcumin significantly (p<0.05) reduced the tumour burden, tumour incidence and tumour volume, which were further supported by the histopathological findings.

    CONCLUSION: MEMM demonstrated chemoprevention possibly via its antioxidant and anti-inflammatory activities, and the action of flavonoids like quercitrin.

    Matched MeSH terms: 9,10-Dimethyl-1,2-benzanthracene
  10. Hamizah S, Roslida AH, Fezah O, Tan KL, Tor YS, Tan CI
    Asian Pac J Cancer Prev, 2012;13(6):2533-9.
    PMID: 22938417
    Annona muricata L (Annonaceae), commonly known as soursop has a long, rich history in herbal medicine with a lengthy recorded indigenous use. It had also been found to be a promising new anti-tumor agent in numerous in vitro studies. The present investigation concerns chemopreventive effects in a two-stage model of skin papillomagenesis. Chemopreventive effects of an ethanolic extract of A. muricata leaves (AMLE) was evaluated in 6-7 week old ICR mice given a single topical application of 7,12-dimethylbenza(α)anthracene (DMBA 100 μg/100 μl acetone) and promotion by repeated application of croton oil (1% in acetone/ twice a week) for 10 weeks. Morphological tumor incidence, burden and volume were measured, with histological evaluation of skin tissue. Topical application of AMLE at 30, 100 and 300 mg/kg significantly reduced DMBA/croton oil induced mice skin papillomagenesis in (i) peri-initiation protocol (AMLE from 7 days prior to 7 days after DMBA), (ii) promotion protocol (AMLE 30 minutes after croton oil), or (iii) both peri-initiation and promotion protocol (AMLE 7 days prior to 7 day after DMBA and AMLE 30 minutes after croton oil throughout the experimental period), in a dose dependent manner (p<0.05) as compared to carcinogen-treated control. Furthermore, the average latent period was significantly increased in the AMLE-treated group. Interestingly, At 100 and 300 mg/ kg, AMLE completely inhibited the tumor development in all stages. Histopathological study revealed that tumor growth from the AMLE-treated groups showed only slight hyperplasia and absence of keratin pearls and rete ridges. The results, thus suggest that the A.muricata leaves extract was able to suppress tumor initiation as well as tumor promotion even at lower dosage.
    Matched MeSH terms: 9,10-Dimethyl-1,2-benzanthracene
  11. Md Roduan MR, Hamid RA, Sulaiman H, Mohtarrudin N
    Biomed Pharmacother, 2017 Oct;94:481-488.
    PMID: 28779710 DOI: 10.1016/j.biopha.2017.07.133
    Annona muricata, locally known as soursop has been reported to exhibit antiproliferative activities against various cancer cell lines. In this current study, we have investigated the antitumor promotion of various fractions of Annona muricata leaves (AML); hexane (AMLH), dichloromethane (AMLD) and methanol (AMLM) fraction respectively on 7, 12-dimethylbenz[α]anthracene (DMBA) induced and 12-0-tetradecaboylphorbol-13-acetate (TPA) promoted skin tumorigenesis in mice via morphological assessment, biochemical analysis and histopathological evaluation. The results of the study revealed significant inhibition in tumor incidence, tumor burden and tumor volume in the groups received AMLH and AMLD, respectively, and suppressive effects in group received AMLM compared with carcinogen control group at week 21. Superoxide dismutase, catalase, and lipid peroxidation levels were returned to near normal by administration of AML to DMBA/TPA-induced mice. The above findings were supported by histopathological studies, in which the extensive epidermal hyperplasia in carcinogen control group was restored to normal in AML treated groups. Whilst, annonacin, a major annaonaceous acetogenin was found to be the highest in AMLH and AMLD. From the present study, it can be inferred that AML supressed DMBA/TPA-induced skin tumor and this antitumor-promoting activity may be linked to the antioxidant/free radical-scavenging constituents of the extract and annonacin contained in the extracts.
    Matched MeSH terms: 9,10-Dimethyl-1,2-benzanthracene
  12. Sulaiman H, Hamid RA, Ting YL, Othman F
    J Cancer Res Ther, 2012 Jul-Sep;8(3):404-10.
    PMID: 23174723 DOI: 10.4103/0973-1482.103521
    CONTEXT: Ardisia crispa Thunb. A. DC (Myrsinaceae) or locally known as hen's eyes has been used in local folk medicine as a remedy in various illnesses. Previously, it has been reported to inhibit various inflammatory diseases. However, research done on this plant is still limited.
    AIMS: In the present study, the hexane fraction of the A. crispa root (ACRH) was evaluated on the peri-initiation and promotion phases of skin carcinogenesis.
    MATERIALS AND METHODS: This two-stage skin carcinogenesis was induced by a single topical application of 7,12-dimethylbenz(α)anthracene (DMBA) and promoted by repeated treatment with croton oil for 10 weeks in Imprinting Control Region (ICR) mice. Morphological observation would be conducted to measure tumor incidence, tumor burden, and tumor volume. Histological evaluation on the skin tissue would also be done.
    RESULTS: The carcinogen control group exhibited 66.67% of tumor incidence. Although, in the ACRH-treated groups, at 30 mg/kg, the mice showed only 10% of tumor incidence with a significant reduction (P < 0.05) in the values of tumor burden and tumor volume of 2.00 and 0.52 mm(3), respectively. Furthermore, the result was significantly lower than that of the carcinogen and curcumin control. At 100 mg/kg, ACRH showed a comparable result to carcinogen control. On the contrary, at 300 mg/kg, ACRH exhibited 100% tumor incidence and showed a significant elevated (P < 0.05) value of tumor burden (3.80) and tumor volume (14.67 ± 2.48 mm(3)).
    CONCLUSIONS: The present study thus demonstrates that the anti-tumor effect of the chemopreventive potential of ACRH is at a lower dosage (30 mg/kg bwt) in both the initiating and promotion period, yet it exhibits a promoting effect at a higher dosage (300 mg/kg bwt).
    Matched MeSH terms: 9,10-Dimethyl-1,2-benzanthracene
  13. Ramu A, Kathiresan S, Ali Ahmed B
    Phytomedicine, 2017 Sep 15;33:69-76.
    PMID: 28887922 DOI: 10.1016/j.phymed.2017.05.008
    BACKGROUND: Transforming growth factor-β (TGF-β) and its receptors are considered as a novel target in cancer chemotherapy. Gramine, an indole alkaloid, possesses various pharmacological properties including antiproliferative and anticancer. However, the anti-angiogenic property remains unexplored.

    PURPOSE: The present study was designed to evaluate the anti-angiogenic and apoptosis induction properties of gramine through inhibiting TGF-β on DMBA induced oral squamous cell carcinoma (OSCC) in the hamster buccal pouch (HBP).

    METHODS: The effects of gramine on TGF-β signalling in DMBA induced carcinogenic events such as angiogenesis and apoptosis were analysed by studying the mRNA expression using RT-PCR, protein expression by western blot and histopathological analysis using haematoxylin and eosin (H & E) staining.

    RESULTS: Gramine significantly inhibited phosphorylation and nuclear translocation of Smad2 and Smad4 by blocking activity of the TGFβ-RII, RI and activation of inhibitory Smad7. Gramine inhibited angiogenic markers such as MMP-2, MMP-9, HIF-1α, VEGF, and VEGF-R2 as well as increased TIMP-2 expression. Furthermore, gramine induced apoptosis in DMBA induced tumour bearing animals by up regulating the pro apoptotic proteins Bax, cytochrome C, apaf-1, caspase-9 caspase-3 and PARP.

    CONCLUSION: In this study, we clearly demonstrated that gramine treatment diminishes angiogenesis and induces apoptosis in hamster buccal pouch (HBP) carcinogenesis by modulating TGF-β signals.

    Matched MeSH terms: 9,10-Dimethyl-1,2-benzanthracene
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