**7.8 Tocotrienols in skin cancer**

One of the earliest application of tocotrienols is in the protection of skin against ultraviolet rays damage. In recent years, the beneficial effects of tocotrienols against skin cancer had been acknowledged. For example, delta-tocotrienol and its peroxy dimer were discovered to be able to prevent the expansion of melanoma cells [136]. The delta isomer of tocotrienols was demonstrated to trigger G1 cell cycle arrest in A2058 and A375 human melanoma cells. This was achieved through suppression of CDK-4 and activation of caspase-3 pathway [116]. Additional studies had demonstrated that gamma-tocotrienol initiated apoptosis in melanoma cells due to inhibition of NF-κB, EGFR, Id family proteins and JNK signalling pathway [117]. The anticarcinogenic effect of δ-T3 has also been deducted by its capability to induce apoptosis via ER stress in melanoma conditions, either in cellular and animal model research [64, 113].

An animal study had found that intravenous administration of alpha-tocotrienol encapsulated within transferrin-bearing vesicles resulted in exhaustive tumour eradication in 60% of B16-F10 melanoma tumour and lengthened the durability of the mice [137]. The gamma-tocotrienol treatment prevented cell invasion in human melanoma through blockade of mesenchymal markers and reclamation of E-cadherin and γ-catenin [117]. In addition, delta-tocotrienols prevented the synthesis of melanin in B16 melanoma cells through stimulation of ERK signalling pathway, which resulted in the under-expression of melanogenesis-related proteins e.g., microphthalmia-associated transcription factor (MITF), tyrosinase and tyrosinase-related proteins, TYRP-1 and TYRP-2 [138].

Interestingly, it was also discovered that tocomin (a tocotrienol preparation derived from palm oil) facilitated the degradation of melanosomes in melanoma cells by upregulating endosome docking/fusion proteins including syntaxin7, vacuolar protein sorting-associated protein Vps16, Vps33, and Vps41 [114]. Mutually, these studies had indicated the undeniable potential of tocotrienols for the management of skin cancer.

#### **7.9 Other cancers**

Besides the types of cancers mentioned above, tocotrienols were also postulated to be able to prevent and treat other forms of carcinomas. Previous research has indicated that the gamma isomer of tocotrienols was able to initiate apoptosis in neuroblastoma SH-SY5Y cells through several postulated mechanisms [115]. Another previous research had concluded that gamma-tocotrienol negated the effect of NF-κB in squamous cell carcinoma of the tongue, which resulted in

#### *Palm Oil Tocotrienols in Cancer Chemoprevention and Treatment DOI: http://dx.doi.org/10.5772/intechopen.98199*

apoptosis [139]. It was also postulated that delta-tocotrienol triggered apoptosis by means of repression of STAT3 signalling in human bladder cancer [140]. Additionally, it has been concluded that alpha- and gamma-tocotrienol triggered apoptosis in HeLa cervical cancer cells through induction of Bax and IL-6 gene expression, promoting cytochrome c release, and suppression of Bcl-2, cyclin D3, CDK6, and p16 gene expression machinery [141, 142]. Likewise, gamma- and delta-tocotrienol also initiated apoptosis in cervical cancer by stimulating ER stress [143]. In multiple myeloma, gamma-tocotrienol suppressed NF-κB and STAT3 signalling and their associated proteins such as Bcl-2 and cyclin D1, thus indicating its postulated role as a potential alternative therapy for multiple myeloma sufferers [139, 144]. A recent result from a small-scale phase II clinical trial involving patients with ovarian cancers showed that the combination of tocotrienol and bevacizumab increased the rate of disease control, progression free survival and overall survival significantly [145].
