2.2.8. Skin Cancer

The antimelanogenesis property of sesamin, was evaluated in comparison to recognized depigmenting agents, kojic acid and β-arbutin. Its ability to function as a sunscreen was investigated through the measurement of UV absorption. Its effects against tyrosinase activity through mushroom and cellular tyrosinase were also observed. The results showed that sesamin was able to absorb ultraviolet in the UVB range with an absorbance intensity of approximately 1.3 at 290 nm, as opposed to the absorbances of kojic acid and β-arbutin equal to 0.2 at 300 nm. Sesamin also exhibited a slight inhibitory effect against tyrosinase. In the same study above, similar antimelanogenesis findings were observed for sesamol. The lignan was also able to absorb ultraviolet in the UVB range with an absorbance intensity of 0.8 at 300 nm, four folds higher than that of kojic acid and β-arbutin. Its inhibition of mushroom tyrosinase activity in vitro was shown to be concentration-dependent just like with kojic acid. The IC50 values for sesamol and kojic acids were 0.33 μg/mL and 6.15 μg/mL, respectively. On the other hand, β-arbutin did not exhibit an inhibitory activity, leading to the conclusion that sesamol has the greatest effect against tyrosinase enzyme [162].

To further assess the ability of sesamol, its cytotoxicity on Vero and SK-MEL2 cell lines were examined. Cytotoxicity of sesamol to Vero cell line was 22.8% after 48 h of treatment, while at a concentration range of 600–800 μg/mL, its cytotoxicity to SK-MEL2 cell line was between 42–97%, with an IC50 value of 608.93 μg/mL. Sesamolin, another lignan, was also tested for its antimelanogenesis activity. Similar with the results in the inhibition of mushroom tyrosinase activity, the sesame lignans and kojic acid obstructed the activity of cellular tyrosinase, while β-arbutin was negative. In line with this, sesamolin was also found to manifest the highest inhibition equal to 50% compared to the other two sesame compounds with only 23% of inhibition. Inhibition of melanin pigment was also investigated among the test compounds and sesamolin showed the most favorable inhibition performance at 25 μg/mL. Other proteins involved in melanogenesis, TRP-1 and TRP-2, were also exposed to the sesame compounds and their levels in SK-MEL2 cells were analyzed using Western blot analysis. It was illustrated that sesamolin lowered TRP-1 and TRP-2 protein levels by 36% and 15%, respectively. Sesame oil was also tested against SK-MEL cells [162], while sesaminol was tested against the SK-MEL-28 cell line, which was found to reduce cyclin D1 expression at a concentration of 100 μM within one to two days of incubation period [132].

Studies have shown that essential polyunsaturated fatty acids such as linoleic acid are capable of exhibiting antiproliferative activity against malignant cell lines. It was also reported that sesame oil is made up of 96% triglycerides and around 90% of its esterified fatty acids are oleic and linoleic acids in an approximately equal proportion. In line with this, sesame oil was proven to manifest greater growth inhibitory effect against melanoma cells than compared to its effect on normal melanocytes. An incubation period of five days showed that the average growth rate of melanoma cells and normal cells were 2.6 and 2.2, respectively [163]. Further investigation on the pathway of inhibition, however, was not executed. In a similar study, the effect of sesamin, sesamol and sesamolin on the synthesis of melanin in mouse melanoma B16F10 cells was observed and only sesamol showed a significant inhibitory effect, which was approximately 63% of the synthesis at 100 μg/mL. The production of melanin was halted by sesamol by inhibiting the specific activities of mushroom tyrosinase, monophenolase and diphenolase. At the same concentration, sesamol was also able to disrupt the viability of the cells by 60% as it was found to exhibit an apoptotic effect [164].

The chemopreventive capability of sesamol, along with sesame oil and two other products, against two-stage skin carcinogenesis of mice was also inspected in vivo. The two-stage skin carcinogenesis initiated by 7,12-dimethylbenz(a)anthracene (DMBA) and promoted by the tumor promoter 12-*O*-tetradecanoylphorbol-13-acetate (TPA) was exposed to resveratrol, sesamol, sesame oil and sunflower oil. Ten weeks of treatment and prior to TPA promotion, the mice showed gross tumor incidence of 20%, 20%, 30% and 20%, respectively, against the 100% control group. After 20 weeks of treatment, only resveratrol and sesamol manifested more than 30% and 10% inhibitory potential, respectively. The ability of the compounds to cancel TPA tumor promotion and impede tumor latency further demonstrated their chemopreventive effects [165]. In-depth mechanisms of action of the products involved against the proliferation of skin papillomas in the mice have not been provided. To test sesamol's impact on the process of neoplastic development, an ex vivo research on the permeation of sesamol to the LACA mice skin was assessed by using sesamol solution and cream base sesamol-loaded solid lipid nanoparticles (S-SLN), while an in vivo method utilized sesamol solution, sesamol ointment and S-SLN. Ex vivo skin permeation of sesamol as a free drug solution was recorded to be much higher than that of S-SLN, which has three times higher skin retention and a 40% drop on the flux. This proposes that SLN is a potential transport service for sesamol. This is consistent with the results of the in vivo study wherein the number of papillomas on the dorsal skin of the mice was checked and there was 0% incidence of skin tumors [158].

#### 2.2.9. Others

Attempts to apply sesamin against pancreatic cancer and skin cancer were also executed. In 1994, pancreatic carcinogenesis initiated with *N-*nitrosobis (2-oxoproyl) amine (BOP) was observed in vivo by controlled diet of Syrian golden hamsters. The effect of sesamin-supplemented diet, a strategy to lower cholesterol levels, on the progress of the pancreatic cancer was evaluated. However, within a four-month period of treatment, it was concluded that although sesamin successfully lowered the cholesterol contents, this did not have any significant effect on BOP-initiated pancreatic cancer in

hamsters [166,167]. Even so, the study emphasizes that the period of observation was done on a short term, which basis and suggests that favorable results possibly occur in a time-dependent manner. In line with this, a more recent study reported that sesamin was able to suppress the growth of pancreatic cancer MiaPaCa-2 cells with an IC50 value of 58.3 μmol/L [129].

The antitumor effect of sesamol was also determined using MA-10 cells, a mouse Leydig tumor cell line. Morphological changes caused by sesamol were observed and cells without sesamol treatment showed signs of normal cell growth phenomena, while those treated with sesamol appeared differently, depending on the duration of the treatment. Plasma membrane blebbing was seen after 12 h of treatment. These findings suggest the apoptotic property of sesamol. To confirm this, MA-10 cells viability against sesamol treatment was assessed. It was then revealed that sesamol is capable of inducing the death of MA-10 cells and that the dose of sesamol and the time of treatment are significant factors that affect the performance of sesamol. Flow cytometry showed DNA fragmentation at the subG1 phase of the cell cycle and verified the apoptosis of MA-10 cells. Similar with the established pathways of other studies, the activation of caspase-3 expression was also observed, consequently inducing apoptosis [168].

The following table (Table 4) provides a summary of the anticancer activities of the lignans of sesame, including their mechanisms of action against each cancer cell line discussed above:




**Table 4.** *Cont.*

#### **3. Conclusions**

The bioactive components of *Sesamum indicum* L., such as sesamin, sesaminol, sesamol and sesamolin, play essential roles in combating different types of biological and pharmacological concerns and are able to exhibit promising medicinal properties against the diseases. One of the notable properties of sesame lignans is anti-inflammation. Inflammation is a defense mechanism of a body against foreign substances and chronic inflammation persist to different kind of diseases. Sesame lignans hinder the propagation of inflammatory cytokines and inflammatory mediators, which further leads to alleviating inflammatory-related diseases such as osteoarthritis, cardiovascular disease, neurodegenerative disease, inflammatory bowel disease, diabetic eye disease, lung disease and liver disease. Other sesame extracts apart from the sesame lignans also exhibit mitigation of inflammatory-related pathways. These are proven by the in vivo and in vitro models of inflammatory-induced systems. Another alarming complication that can be instigated by inflammation is cancer. Cancer, which is the abnormal growth of the cells, may develop when the body suffers from DNA damage caused by the chemicals released during inflammation. Interestingly, it was also revealed that the lignans of sesame manifest anticancer activities against different cancer cell lines with different mechanisms of action. Both in vitro and in vivo studies have presented that the lignans are capable of inhibiting the growth of the cancer cells by down-regulating protein expressions, by suppressing the production of gene products, and through cell cycle arrest. Consequently, the lignans also induce either necrosis or apoptosis to the cells, inflicting an antiproliferation effect. Sesame lignans have been proven to manifest these anticancer effects against the tumor cells of lung cancer, breast cancer, colon cancer, prostate cancer, cervical cancer, blood cancer, skin cancer and even pancreatic cancer. With all things considered, sesame proves that food can indeed become a medicine and that foods do not only possess nutritional value, but they also have medicinal worth. The lignans of sesame that manifest anti-inflammatory and anticancer properties and the specific diseases that they act against are summarized in Figure 2 below:

**Figure 2.** Anti-inflammatory and anti-cancer activities of major sesame lignans.

**Author Contributions:** M.-S.W., L.B.B.A., M.Y.U.B.: developed the concept for the review, wrote manuscript and original draft preparation; K.A.D.C.-C., C.-L.H, L.-L.Y.: contributed literature search and data curation; P.-W.T.: supervision and final revision.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
