Sensitization of recombinant human tumor necrosis factor-related apoptosis-inducing ligand-resistant malignant melanomas by quercetin

Abstract

Malignant melanoma is the most commonly diagnosed skin cancer associated with a high rate of metastasis. Low-stage melanoma is easily treated, but metastatic malignant melanoma is an extremely treatment-resistant malignancy with low survival rates. The application of recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) for the treatment of metastatic malignant melanoma holds considerable promise because of its selective proapoptotic activity towards cancer cells and not nontransformed cells. Unfortunately, the clinical utilization of rhTRAIL has been terminated due to the resistance of many cancer cells to undergo apoptosis in response to rhTRAIL. However, rhTRAIL-resistance can be abrogated through the cotreatment with compounds derived from ‘Mother Nature’ such as quercetin that can modulate cellular components responsible for rhTRAIL-resistance. Here, we show that rhTRAIL-resistant malignant melanomas are sensitized by quercetin. Quercetin action is manifested by the upregulation of rhTRAIL-binding receptors DR4 and DR5 on the surface of cancer cells and by increased rate of the proteasome-mediated degradation of the antiapoptotic protein FLIP. Our data provide for a new efficient and nontoxic treatment of malignant melanoma.

A network pharmacology perspective for deciphering potential mechanisms of action of Solanum nigrum L. in bladder cancer

“…Quercetin, a flavonoid, belongs to an extensive class of polyphenolic compounds. It can not only inhibit the apoptosis and proliferation of numerous malignant cells, including BC and tumor growth in animal models through multiple signaling pathways [ 37 ], such as the AMPK [ 38 ], PI3K/Akt [ 39 ], and JNK pathways [ 40 ], but can also enhance the sensitivity of other anti-cancer agents and reverse the drug resistance of cancer cells [ 40 ]. Based on the I–T network, quercetin was linked to all targets with the highest degree among all selected ingredients, suggesting potential synergies between quercetin and all the other ingredients.…”

A Network Pharmacology Approach to Uncover the Potential Mechanism of Yinchensini Decoction

“…In vitro, quercetin can not only inhibit the proliferation and apoptosis of many tumor cells through multiple signaling pathways, such as the Wnt signaling pathway (cholangiocarcinoma) and the JNK signaling pathway, but enhance the sensitivity of other anticancer drugs and reverse the drug resistance of tumor cells [5]. What is more, Quercetin has all kinds of pharmacological activities such as antioxidant and hepatoprotective effects [6].…”

Ursolic Acid Promotes the Sensitization of rhTRAIL-resistant Triple-negative Breast Cancer

“…Investigations have focused on applying additional compounds, including "mother-nature"-derived compounds, to enhance rhTRAIL's pro-apoptotic effects in an array of cancer cells including breast cancer cells (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(33)(34)(35). Our laboratory has specifically examined the impact of quercetin in breast cancer and malignant melanoma and silibinin in breast cancer to sensitize cancer cells resistant to rhTRAIL (7,8,17). The natural compound UA is a triterpenoid, and it should be noted that other laboratories have studied the positive impact of synthetic triterpenoids in combination with TRAIL on cancer cells in vitro and in vivo (33)(34)(35).…”

“…In our previous studies, the ability of "mother nature"derived compounds Quercetin (Q) and silibinin to sensitize cancers resistant to rhTRAIL to apoptosis induced by rhTRAIL has been demonstrated (7,8,17). Q enhanced DR4 and DR5 expression in rhTRAIL-resistant malignant melanoma, and DR5 expression in rhTRAIL-resistant TNBC.…”