The results of this study reveal that artichoke inhibits the growth of melanoma cell line HTB-72 through the upregulation of p21 and p27 and downregulation of cdk4 and survivin. To our knowledge this is the first study to evaluate the anti-tumor impact of AE on slowing down the proliferation and altering apoptosis of melanoma cells. This is also the first study to explicate the molecular mechanism of the impact of AE on HTB-72.
The intricate mechanism of cell cycle progression has been well established through a series of checkpoints of pro- and anti-proliferative molecules [16–18]. The molecules p21 and p27 work as inhibitory molecules in the G1 to S phase checkpoint and were both increased by AE. Both p21 and p27 work by inhibiting cdk/cyclin complexes that are necessary for cell cycle progression. p27 works only at the cdk2/Cyclin E complex while p21 works at both cdk2/Cyclin E and cdk4/6/Cyclin D complex [19–22]. As seen in previous studies, the overexpression of cyclin E has been linked to several types of cancers including breast, colon, bladder, skin, and lung [23]. These findings indicate possible future areas of cancer study for the application of AE with radiation therapy.
Cdk4 was decreased by AE and functions as a promoter of the cell cycle at the G1 to S phase checkpoint. Cdk4 creates a complex with cyclin D and phosphorylates Rb which allows the progression of G1 to S phase [24]. Studies have shown that mutations of p16, a cdk4/6 inhibitor or an activating mutation of cdk4 have a relationship with melanoma, in particular hereditary melanoma [25–31].
Survivin works at the G2/M checkpoint and normally functions as a member of the inhibitor of apoptosis protein family. This protein is able to inhibit caspases and block cell death. Survivin is elevated in many cancers and is often associated with poor outcomes [41]. In the presence of AE, survivin levels were notably decreased. This finding further reinforces AE ability to promote apoptosis in HTB-72 melanoma cell line.
Although the results of this study are highly promising, there are limitations that should be addressed. Only one cell line, HTB-72, was used in this experiment. Future studies should expand to study other melanoma cell lines to evaluate the effects of artichoke. Another limitation of this study was that no animal models were used. Subsequent studies should aim to utilize animal models to further evaluate the mechanistic effects of artichoke on melanoma proliferation. With these points considered, this study is a good start to exploring the impact of artichoke on melanoma.
One area of future study is using AE as a radiosensitizer. When treating melanoma, radiation is rarely used as first-line therapy due to its classification being traditionally radio resistant. However, in cases where surgery cannot be performed, radiation can be used as first-line or postoperative adjuvant [5, 6]. Radiation therapy also is important in cases of advanced and metastatic melanoma, in particular with whole brain radiation therapy for brain metastasis. With radiation therapy comes various risks and damage to healthy tissue. Some of these side-effects include: localized skin irritation, erythema, edema, changes in pigmentation, and chronic issues such as loss of appendages and tissue retraction leading to mobility limitations [7]. Although there have been many studies that looked at possible radiosensitizers for melanoma, there has not yet been any promising improvement in outcomes for patients with metastatic melanoma [8]. Increasing melanoma susceptibility to radiation through the use of radiosensitizers may allow lower doses of radiation which can in turn lessen the possible side-effects. Further studies are needed to deduce if AE can play a role as a potential radiosensitizer in melanoma as well as other cancers.
In conclusion, AE reveals anti-tumor activity on melanoma through aiding apoptosis and inhibiting cell proliferation in vitro. The results of this study highlight the potential use of AE in the treatment of melanoma. In conjunction with these promising results, further clinical studies may lead to an increase in the role of AE in the treatment of melanoma and other malignancies.