Synthesis, Inverse Docking-Assisted Identification and in vitro Biological Characterization of Flavonol-based Analogs of Fisetin as c-Kit, CDK2 and mTOR Inhibitors against Melanoma and Non-melanoma Skin Cancer

Non-melanoma skin cancers (NMSCs) are the leading cause of skin cancer-related morbidity and mortality. Effective strategies are needed to control NMSC occurrence and progression. Non-toxic, plant-derived extracts have been shown to exert multiple anti-cancer effects. Graviola (Annona muricata), a tropical fruit-bearing plant, has been used in traditional medicine against multiple human diseases including cancer. The current study investigated the effects of graviola leaf and stem extract (GLSE) and its solvent-extracted fractions on two human NMSC cell lines, UW-BCC1 and A431. GLSE was found to: i) dose-dependently suppress UW-BCC1 and A431 cell growth, motility, wound closure, and clonogenicity; ii) induce G0/G1 cell cycle arrest by downregulating cyclin/cdk factors while upregulating cdk inhibitors, and (iv) induce apoptosis as evidenced by cleavage of caspases-3, -8 and PARP. Further, GLSE suppressed levels of activated hedgehog (Hh) pathway components Smo, Gli 1/2, and Shh while inducing SuFu. GLSE also decreased the expression of pro-apoptotic protein Bax while decreasing the expression of the anti-apoptotic protein Bcl-2. We determined that these activities were concentrated in an acetogenin/alkaloid-rich dichloromethane subfraction of GLSE. Our data identify graviola extracts and their constituents as promising sources for new chemopreventive and therapeutic agent(s) to be further developed for the control of NMSCs

Download Full-text

Graviola (Annona muricata) Exerts Anti-Proliferative, Anti-Clonogenic and Pro-Apoptotic Effects in Human Non-Melanoma Skin Cancer UW-BCC1 and A431 Cells In Vitro: Involvement of Hedgehog Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms19061791 ◽

2018 ◽

Vol 19 (6) ◽

pp. 1791 ◽

Cited By ~ 5

Author(s):

Jean Chamcheu ◽

Islam Rady ◽

Roxane-Cherille Chamcheu ◽

Abu Siddique ◽

Melissa Bloch ◽

...

Keyword(s):

Skin Cancer ◽

Hedgehog Signaling ◽

Annona Muricata ◽

A431 Cells ◽

Non Melanoma Skin Cancer ◽

Apoptotic Effects ◽

Melanoma Skin

Download Full-text

Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel–Hyaluronan Bioconjugate: In Vitro Evaluation in Non-Melanoma Skin Cancer

Biomedicines ◽

10.3390/biomedicines9060597 ◽

2021 ◽

Vol 9 (6) ◽

pp. 597

Author(s):

Barbara Bellei ◽

Silvia Caputo ◽

Emilia Migliano ◽

Gianluca Lopez ◽

Valeria Marcaccini ◽

...

Keyword(s):

Skin Cancer ◽

Apoptotic Cell ◽

Wnt Signaling Pathway ◽

Dermal Fibroblasts ◽

Carcinoma Cells ◽

Cancer Associated Fibroblasts ◽

Innovative Therapy ◽

Non Melanoma Skin Cancer ◽

Melanoma Skin

Background: Cancer-associated fibroblasts (CAFs) facilitate many aspects of cancer development by providing a structural framework rich in bioactive compounds. There are emerging studies proposing a combination of conventional anti-cancer therapies directed against neoplastic cells to molecules targeting tumor microenvironments. Methods: The study evaluated the pharmacological properties of the anti-tumor agent paclitaxel conjugated to hyaluronic acid (HA) regarding non-melanoma skin cancer (NMSC) and the surrounding fibroblasts. This molecule, named Oncofid-P20 (Onco-P20), preferentially targets cells expressing high levels of CD44, the natural ligand of HA. Results: Consistent with paclitaxel’s mechanism of action involving interference with the breakdown of microtubules during cell division, highly sensitive carcinoma cells rapidly underwent apoptotic cell death. Interestingly, less sensitive cells, such as dermal fibroblasts, resisted the Onco-P20 treatment and experienced a prolonged growth arrest characterized by morphological change and significant modification of the gene expression profile. Onco-P20-treated fibroblasts exhibited reduced growth factor production, downmodulation of the Wnt signaling pathway, and the acquisition of a marked pro-inflammatory profile. Independently of direct exposure to taxol, in the presence of Onco-P20-treated fibroblasts or in their conditioned medium, carcinoma cells had a reduced proliferation rate. Similar to NHF, fibroblasts isolated from skin cancer lesions or from adjacent tissue acquired anti-neoplastic activity under Onco-P20 treatment. Conclusion: Collectively, our data demonstrate that Onco-P20, exerting both a direct and an NHF-mediated indirect effect on carcinoma cells, is a candidate for an innovative therapy alternative to surgery for the treatment of NMSC.

Download Full-text

Delineating cell behavior and metabolism of non-melanoma skin cancer in vitro

In Vitro Cellular & Developmental Biology - Animal ◽

10.1007/s11626-019-00416-6 ◽

2020 ◽

Vol 56 (2) ◽

pp. 165-180 ◽

Cited By ~ 1

Author(s):

Tatiana Mendez ◽

Shawheen Saffari ◽

Janet M. Cowan ◽

Nora M. V. Laver ◽

James D. Baleja ◽

...

Keyword(s):

Skin Cancer ◽

Cell Behavior ◽

Non Melanoma Skin Cancer ◽

Melanoma Skin

Download Full-text

Assessment of the risk and characterization of non-melanoma skin cancer in Kindler syndrome: study of a series of 91 patients

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1158-6 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 5

Author(s):

Sara Guerrero-Aspizua ◽

Claudio J. Conti ◽

Maria Jose Escamez ◽

Daniele Castiglia ◽

Giovanna Zambruno ◽

...

Keyword(s):

Skin Cancer ◽

Kindler Syndrome ◽

Non Melanoma Skin Cancer ◽

Melanoma Skin

Download Full-text

Human Papillomaviruses and Non-Melanoma Skin Cancer: Basic Virology and Clinical Manifestations

Disease Markers ◽

10.1155/2007/942650 ◽

2007 ◽

Vol 23 (4) ◽

pp. 247-259 ◽

Cited By ~ 105

Author(s):

Ingo Nindl ◽

Marc Gottschling ◽

Eggert Stockfleth

Keyword(s):

Skin Cancer ◽

Cell Carcinoma ◽

Uv Radiation ◽

Clinical Manifestations ◽

Human Papillomaviruses ◽

Induced Mutations ◽

Non Melanoma Skin Cancer ◽

Hpv Types ◽

Melanoma Skin

Human papillomaviruses (HPV) infect cutaneous and mucosal epithelia and induce benign and malignant lesions. Non-melanoma skin cancer (NMSC), encompassing basal cell carcinoma and squamous cell carcinoma (SCC), is the most frequent cancer in the Caucasian population, and the incidence has increased dramatically worldwide. Ultraviolet (UV) radiation is a major risk factor for NMSC, and cutaneous HPV is also considered to play an active role during the pathogenesis of these cancers. The first evidence for the involvement of HPV in NMSC was reported in patients with Epidermodysplasia verruciformis (EV). HPV types detected in skin tumours of these patients are referred to as EV/cutaneous HPV types belonging to the beta- and gamma-papillomaviruses (PV). Epidemiological studies have shown a higher risk of several EV/cutaneous HPV types for NMSC. Furthermore,in vitroand animal models show transforming properties of some PV types. The anti-apoptotic activities, and the delay of DNA repair mechanism caused by some EV/cutaneous HPV E6 proteins in response to UV-induced mutations, may lead to the persistence of DNA-damaged keratinocytes. Thus, specific EV/cutaneous HPV types as co-factors in association with UV-radiation and the immune system seem to be involved in the early pathogenesis of cutaneous SCC.

Download Full-text

Simultaneous targeting tumor cells and cancer-associated fibroblasts with a Paclitaxel-Hyaluronan bioconjugate: in vitro evaluation in non-melanoma skin cancer

10.21203/rs.3.rs-39623/v2 ◽

2020 ◽

Author(s):

Barbara Bellei ◽

Silvia Caputo ◽

Emilia Migliano ◽

Gianluca Lopez ◽

Valeria Marcaccini ◽

...

Keyword(s):

Skin Cancer ◽

Tumor Cells ◽

Apoptotic Cell ◽

Dermal Fibroblasts ◽

Carcinoma Cells ◽

Cancer Associated Fibroblasts ◽

Wnt Signal Pathway ◽

Non Melanoma Skin Cancer ◽

Melanoma Skin

Abstract Background: Cancers are complex organs which encompass not only the tumor cells but also cells within the surrounding stroma. Such cells, mainly cancer associated fibroblasts (CAFs) and immune infiltrating cells, facilitate many aspects of cancer development providing a structural and supportive framework rich of bioactive compounds. So far, there are emerging studies proposing the combination of conventional anti-cancer therapy, directed against neoplastic cells, to molecules targeting tumor microenviroment.Methods: The study was designed to evaluated the pharmacological properties of the anti-tumor agent paclitaxel conjugated to hyaluronic acid (HA) on non-melanoma skin cancer (NMSC) and on the surronding dermal fibroblasts. This molecule, named Oncofid-P20 (Onco-P20), targets preferentially cells expressing high level of CD44, the natural ligand of HA.Results: Consistent with paclitaxel’s mechanism of action involving interferences with the normal breackdown of microtubules during cell division, highly sensible carcinoma cells underwent rapidly to apoptotic cell death. Interestingly, less sensible cells such as dermal fibroblasts resisted to the Onco-P20 treatment and experirenced a prologed growth arrest characterized by morphological change and significant modification of the gene espression profile that partially overlaps with that of senescent cells. Onco-P20-treated fibroblasts lowered growth factors production, down-modulate Wnt signal pathway and acquired a marked pro-inflammatory profile. Independently to the direct exposure to taxol, in presence of Onco-P20-treated fibroblasts or their conditioned medium, carcinoma cells reduced the proliferation rate. Similar to NHF, fibroblasts isolated from skin cancer tumor lesion or from tissue adjacent to the tumor acquired an anti-neoplastic activity under Oncofid-P20 treatment.Conclusion: Collectively, our data demonstrated that Onco-P20, exerting both a direct and a NHF-mediated indirect paracrine effect on carcinoma cells, is a good candidate for an innovative therapy alternative to surgery for treatment of NMSC.

Download Full-text