Asian Pacific Journal of Cancer Prevention. 2013; 14(4): 2301-5

Isolation of a Quinone-rich Fraction from Ardisia crispa Roots and its Attenuating Effects on Murine Skin Tumorigenesis.

Looi Ting Yeong1, Roslida Abdul Hamid1, Latifah Saiful Yazan1,2, Huzwah Khaza’ai1

1 Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor Darul Ehsan, Malaysia

2 Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Selangor Darul Ehsan, Malaysia

 

ABSTRACT:

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.

PMID: 23725131

 

SUPPLEMENT:

Quinones are ubiquitous in nature and they are generally cytotoxic and/or genotoxic. A handful of these compounds have been targeted towards tumors and benefited therapeutically as anticancer agents, such as doxorubicin and mitomycin [1]. In this study, an evergreen shrub named Ardisia crispa (Figure 1) was selected for it has been shown to exert several biological effects encompassing anti-inflammatory and antitumor. A quinone compound (2-methoxy-6-undecyl-1,4-benzoquinone) isolated previously from the root hexane fraction of the plant was also shown to be pharmacologically active as an anti-inflammatory agent. Considering the potential of quinone compound in anticancer and the close association between inflammation and cancer, it raised our interest to perform an in vivo study to evaluate antitumor effects of a fraction abundant in that quinone compound via the commonly used two-stage mouse skin tumorigenesis model.

The model is based on the concept that the process of cancer development occurs via two stages: an ‘initiation’ stage where a normal cell undergoes permanent genetic changes; and a subsequent ‘promotion’ stage where the genetically altered cell is imperiled upon further provocation by tumor promoter, leading to increased cell number and eventual formation of papilloma/tumor. List of carcinogens has been identified and one of the culprits is attributable to exposure to polycyclic aromatic hydrocarbons (PAHs) in grilled and smoked food, tobacco smoke and automobile exhaust. In research, these processes (initiation and promotion) are attained chemically by application of 7,12-dimethylbenz[α]anthracene (DMBA) (tumor initiator) and croton oil or phorbol esters (tumor promoters) onto the skin of laboratory animals, most commonly mice.

By applying quinone-rich fraction (QRF) during different stages of carcinogenesis viz. initiation, promotion and initiation/promotion, we found that QRF did not exert inhibitory effect against mouse skin tumor development during the initiation stage, but significant reductions in tumor formation were noted upon application of QRF during both promotion and initiation/promotion stages. We proposed that short-term application of QRF was insufficient to protect cellular DNA from DMBA insults, a condition that was observed upon application of QRF for a period of 14 days, prior to and after DMBA application; but long-term (> 20 weeks) of QRF treatment could have attenuated the condition, possibly by targeting multiple signaling pathways such as epidermal growth factor (EGF), proinflammatory cytokines and prostaglandins, thus leading to tumor suppressive effects.

Although effects of QRF during both promotion and initiation/promotion protocols seemed comparable, we favored QRF as a more effective agent against the ‘promotion’ stage in view of the fact that it caused prominent delay in tumor formation when QRF was applied during that period. Because ‘promotion’ stage is a reversible process, we are optimistic in the significance of Ardisia crispa as a potential antitumor promoting agent that could prevent oneself from further devastating cancerous effects. Anyhow, such notion is still limited by in-depth mechanism(s) study before the plant can be clinically trialed. It remains one of our goals, in the near future, to explicate the possible mechanism(s) underlying such effects, particularly by targeting antioxidant/detoxication enzymes and the related Nrf2-regulatory pathways.

References:

1. Sinha, B. K. and Mimnaugh, E. G. (1990). Free radicals and anticancer drug resistance: oxygen free radicals in the mechanisms of drug cytotoxicity and resistance by certain tumors. Free Radical Biology and Medicine 8(6): 567-581.

2. Li Na Herbs. Pokok Mata Itik (Ardisia crispa). http://linaherbs.blogspot.com/2010/02/pokok-mata-itik-ardisia-crispa.html. Retrieved on 28 July 2013.

 

figure-1Ardisia crispa plant [2].

figure-2 Mouse shaved dorsally for the ease of topical application and absorption of DMBA, croton oil or QRF.

figure-3
Regulatory effects of QRF on tumor incidence, tumor burden, tumor volume and latency period of tumor formation during initiation, promotion and initiation/promotion stages of mouse skin tumorigenesis.

 

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