Squalene helps protect against the chemotherapy-induced toxicity.
- by Dr. Bikul Das
Courtesy of Neoplasia, An International Journal for Oncology Research.
This is a very exciting development. To put it simply, studies show that Squalene helps protect against the chemotherapy-induced toxicity. This opens the very huge chemotherapy market to the benefits of Issho Genki Squalene iP6. We will keep you updated on this. For more on this click here.
Introduction
Myelosuppression is a major toxicity for most chemotherapy regimens.
Myelotoxicity is associated with morbidity, mortality, cost,
and, most importantly, with reduced chemotherapy dose intensity
and treatment failure [1,2]. The reduction in dose intensity may compromise
treatment outcome including disease control and survival
in patients with curable malignancies [1]. Among the most commonly
used myelosuppressive drugs are the platinum derivatives cisdiammine
(cyclobutane-1,1-dicarboxylato) platinum(II) (carboplatin)
and cis-diamminedichloroplatinum(II) (cisplatin) [3]. Carboplatin is
a second-generation platinum complex having substantial myelosuppressive
effects. The toxicity is cumulative in nature and can occur in
18% to 25% of cases [3]. Treatment with high-dose carboplatin
(>1200 mg/m2) leads to myelosuppression in >90% of cases [4]. Cisplatin
is the first generation platinum compound having mild myelosuppressive
effects (5-6% cases). The toxicity is correlated with peak
levels of the drug in the first 2 weeks of treatment [4,5], and its incidence
and severity dramatically increase in patients under dialysis
(25-100% cases) [5,6] and when used in combination with carboplatin
[7].
One of the known mechanisms of toxicity of platinum drugs such as cisplatin and carboplatin is due to cross-linking with nucleic acids and proteins. Both cisplatin and carboplatin are platinum(II) complexes with two ammonia groups in the cis position. Cisplatin has two chloride groups, which are replaced by water molecules in an intracellular aquation reaction. The reaction is driven by the high concentration of water and low concentration of chloride in the tissues. The aquated platinum complex can then react with a variety of macromolecules including RNA, DNA, and protein. The cytotoxicity of cisplatin is correlated closely with platinum DNA interstrand bifunctional N-7 adducts at d(GpG) and d(Apg) [8]. However, so far, the types of DNA lesions responsible for the cytotoxicity of cisplatin have not been clearly established [3]. Other toxic effects of cisplatin in vitro– cultured cell growth includes attenuation of mitochondrial function and the release of reactive oxygen species in the cells [9,10]. Carboplatin has a similar mechanism of action like cisplatin [3].
The mechanism of platinum-induced myelosuppression is not clearly known. Evans et al. [11] reported that after a single dose of cisplatin treatment (4-20 mg/kg) in hybrid mice (C57BL × BALB/c), the light-density bone marrow (LD-BM)–derived colony-forming units (CFUs) were depleted significantly. Nowrousian and Schmidt [12] found similar results of the depletion of the CFUs suggesting that cisplatin may target the hematopoietic stem cell fraction leading to myelosuppression. We previously reported that cisplatin treatment exerts significant toxicity on the hematopoietic stem cell fraction in vitro [13]. Carboplatin has also been found to target the hematopoietic stem cell fraction both in vitro and in vivo [3,14,15]. The mechanism of platinum-induced toxicity on hematopoietic stem cells may be related to its DNA cross-linking and generation of oxidative stress products such as malondialdehyde [16]. Carboplatin may have a similar mechanism of oxidative stress induction as cisplatin [3], and it has been found to decrease glutathione (GSH) level in rat kidney [17] and bone marrow (BM) cells [18]. Antioxidants GSH and metallothioneins are found to prevent cisplatin and carboplatin–induced toxicity [19–22]. Hence, the clinical use of antioxidants have been suggested to reduce cisplatin and carboplatin–induced myelosuppression [21,23–28].
Squalene is an isoprenoid antioxidant that is secreted in human sebum, where it may protect skin from UV radiation [29]. Dietary squalene has been found to have radioprotective activity [30] and exerts anticarcinogenic activity against several compounds by enhancing cellular antioxidant status [31–34]. Our in vitro studies in squalene-mediated cytoprotection indicate that squalene (12.5- 25 μM) has selective cytoprotective activity; it protected BM colonies from cisplatin-induced toxicity without protecting neuroblastoma colonies [13]. Importantly, the cytoprotective activity of squalene was equivalent to GSH, a major intracellular antioxidant and detoxifying agent [20]. Furthermore, squalene may have antitumor activity. It has been previously shown that squalene inhibited murine sarcoma growth and survival in a mouse model [35–38]. We found that squalene inhibits the in vitro growth of the NBL-S neuroblastoma cell line [13].
Such differential normal tissue protective, anticarcinogenic, and antitumor activities make squalene a potential cytoprotective agent against chemotherapeutic-induced myelotoxicity [13,29]. To test this possibility, we investigated the in vivo protective activity of squalene in a mouse model of platinum-induced myelotoxicity. We also investigated the potential protective activity of squalene against platinuminduced toxicity against tumor growth in vivo.
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