ABSTRACT

1. INTRODUCTION TO CANCER

Cancers are multifactorial diseases of various etiologies. They arise largely as a result of acquired genetic changes that alter cell function leading neoplastic cells to gain survival or growth advantages [1]. For cancer cells to survive, the generation of new blood vessels (angiogenesis) is required. Cancer leads to death mostly through tumor cell spread to distal organs (metastasis). Various pathways are disrupted in tumor development, which result from unbalanced programmed cell death, disordered signaling pathways, angiogenesis and poor immune response against cancer. Most of the chemotherapeutic agents used in cancer treatment target these major deregulated pathways. Unfortunately, as many of these therapies cause severe side effects, the toxicities limit the dose and thus the efficacy of treatment. Therefore, there is strong interest in developing better-tolerated anti-cancer agents.

2. A ROLE FOR NATURAL PRODUCTS FOR CANCER TREATMENT

Chemotherapy has been a cornerstone of the standard cancer treatment regimens since the 1960s. A variety of chemicals ranging from traditional agents such as methotrexate and folic acid analogues to novel chemicals such as anthracyclines have been used in cancer treatment [2]. Despite promising tumor growth-inhibitory effects in pre-clinical tests, many fail in clinical trials when adverse unexpected side effects are revealed. Traditionally anti-cancer chemotherapy targets rapidly dividing and proliferating cells. Therefore, normal cells which have high-proliferating potential are also affected.

Novel therapeutic agents are designed to target specific molecules (targeted therapy). However, these targeted therapies are not always completely free of side effects either. For instance, vemurafenib, a B-Raf enzyme inhibitor, is specific for oncogenic mutant V600E B-Raf positive melanoma cells. This drug was the first targeted molecular therapy, which was approved for use in advanced stages of melanoma. Although vemurafenib has shown significant beneficial anti-cancer effects, several studies have reported the rapid emergence of acquired resistance and adverse dermatological effects. It also stimulates B-Raf expression in V600E B-Raf negative patients promoting melanoma growth [3,4]. Monoclonal antibodies are another example of targeted therapy and are designed to specifically target the cancer antigens located on tumor cells. Monoclonal antibodies are generally safer than chemotherapy and the side effects caused by them include mild allergic reactions such as urticaria. But they can also cause severe reactions such as infusion reactions and serum sickness. As an example, rituximab (anti-CD20), which is widely used in treating B-cell lymphoma, generally causes only mild toxicities, however, reports have described occasional cases with severe complications such as anaphylactic reactions and myocardial infarction as well as high risk of tumor lysis syndrome in patients who have a high burden of tumor cells in their circulation [5].

Concerns over toxicity, tumor cell resistance and development of secondary cancers from chemotherapeutic chemicals have generated interest in exploiting natural products for cancer treatment. Flavopiridol is a flavonoid derived from the indigenous Indian plant Dysoxylum binectariferum, which inhibits cell cycle progression. It is the first cyclin-dependent kinase (CDK) inhibitor to be approved for use in clinical trials [6]. Natural products are also being tested as adjuvants for use in synergy with chemotherapeutic agents. For example those with immunomodulatory effects can reduce immune suppression and the associated increased risk of infection. In George et al. [7] study, Indukantha Ghritha (IG), a polyherbal preparation consisting of 17 plant components, was used as an adjuvant to cyclophosphamide cancer chemotherapy and shown to stimulate the hematopoietic system and induce leukopoiesis in tumor-bearing mice. When administrated in combination with cyclophosphamide, it reversed myelosuppression induced by cyclophosphamide suggesting its potential to minimize or reverse chemotherapy-induced leukopenia.

Polysaccharides include a large family of diverse biopolymers. They are constituted by monosaccharide residues linked together by O-glycosidic bonds that are found in natural and semi-synthetic structures [8]. Due to structural diversity, polysaccharides display the highest biological properties among macromolecules. Many natural polysaccharides obtained from natural sources such as plants and algae have anti-cancer properties. The multifunctional structure of natural polysaccharides also allows them to be used in conjugation with anti-cancer agents that lack physiochemical and biopharmaceutical properties [8,9].

3. FUCOIDAN

Fucoidan is a natural sulfated polysaccharide that exists mainly in the cell wall matrix of various species of brown seaweed such as mozuku, kombu, limumoui, bladderwrack and wakame [10]. Various forms of fucoidan have also been recognized in some marine invertebrates such as sea urchins [11] and sea cucumbers [12]. The brown seaweeds containing fucoidan are widely consumed as part of the normal diet in East Asia, particularly Japan, China and Korea.