2′-hydroxyflavanone (2HF) is a dietary flavonoid with anticancer activity towards multiple cancers. Here, we report that topically applied 2HF inhibits the growth of intradermal implants of melanoma in immunocompetent mice. 2HF induced apoptosis and inhibited the growth of the human SK-MEL-24 as well as murine B16-F0 and B16-F10 melanoma cell lines in vitro. Apoptosis was associated with depletion of caspase-3, caspase-9, and PARP1 in B16-F0 and SK-MEL-24 cells. Caspase-9 and MEKK-15 were undetected even in untreated B16-F10 cells. Signaling proteins TNFα, and phospho-PDGFR-β were depleted in all three cell lines; MEKK-15 was depleted by 2HF in SK-MEL-24 cells. 2HF enhanced sunitinib (an MEK and PDGFR-β inhibitor) and AZD 2461 (a PARP1 inhibitor) cytotoxicity. 2HF also depleted the Ral-regulated, stress-responsive, antiapoptotic endocytic protein RLIP76 (RALBP1), the inhibition of which has previously been shown to inhibit B16-F0 melanoma growth in vivo. Functional inhibition of RLIP76 was evident from inhibition of epidermal growth factor (EGF) endocytosis by 2HF. We found that topically applied 2HF–Pluronic Lecithin Organogel (PLO) gel inhibited B16-F0 and B16-F10 tumors implanted in mice and caused no overt toxicity despite significant systemic absorption. 2HF treatment reduced phospho-AKT, vimentin, fibronectin, CDK4, cyclinB1, and BCL2, whereas it increased BIM and phospho-AMPK in excised tumors. Several cancer signals are controlled by endocytosis, a process strongly inhibited by RLIP76 depletion. We conclude that 2HF–PLO gel may be useful for topical therapy of cutaneous metastases of melanoma and could enhance the antineoplastic effects of sunitinib and PARP1 inhibitors. The mechanism of action of 2HF in melanoma overlaps with RLI76 inhibitors.

A variety of cutaneous reactions have been described in patients receiving tumor necrosis factor alfa (TNF-α) inhibitors.¹ Asarch A. Gottlieb A.B. Lee J. et al. Lichen planus-like eruptions: An emerging side effect of tumor necrosis factor-a antagonists. J Am Acad Dermatol. 2009; 61 : 104-111 Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar Of particular interest in this scenario is the development of lichen planus and lichen planus–like eruptions. Because TNF-α is recognized as a significant factor in the induction of these dermatoses, their appearance after inhibition of TNF-α is perplexing.² Lora V. Kanitakis J. Latini J. Cota C. Lichen Striatus associated with etanercept treatment of rheumatoid arthritis. J Am Acad Dermatol. 2014; 70 : e90-e92 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The leading theory postulates that a disturbance in the balance between inflammatory cytokines occurs with TNF-α inhibition, leading to increased expression of other cytokines such as interferon.¹ Asarch A. Gottlieb A.B. Lee J. et al. Lichen planus-like eruptions: An emerging side effect of tumor necrosis factor-a antagonists. J Am Acad Dermatol. 2009; 61 : 104-111 Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar ^{,  2} Lora V. Kanitakis J. Latini J. Cota C. Lichen Striatus associated with etanercept treatment of rheumatoid arthritis. J Am Acad Dermatol. 2014; 70 : e90-e92 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar ^{,  3} Joshi R. Interface Dermatitis. Indian J Dermatol Venereol Leprol. 2013; 79 : 349-359 Crossref PubMed Scopus (17) Google Scholar Interferon then induces an endogenous inflammatory response that clinically manifests as a cutaneous lichenoid eruption.¹ Asarch A. Gottlieb A.B. Lee J. et al. Lichen planus-like eruptions: An emerging side effect of tumor necrosis factor-a antagonists. J Am Acad Dermatol. 2009; 61 : 104-111 Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar ^{,  2} Lora V. Kanitakis J. Latini J. Cota C. Lichen Striatus associated with etanercept treatment of rheumatoid arthritis. J Am Acad Dermatol. 2014; 70 : e90-e92 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar ^{,  3} Joshi R. Interface Dermatitis. Indian J Dermatol Venereol Leprol. 2013; 79 : 349-359 Crossref PubMed Scopus (17) Google Scholar

Space exploration exposes astronauts to unique conditions such as microgravity and space radiation, potentially influencing gene expression and triggering carcinogenesis. Paradoxically, these extreme environments could uncover other pro-treatment aspects of cancer biology. Despite numerous reviews addressing these aspects in isolation, a comprehensive synthesis of the effects of space stressors on cancer development is incomplete. This scoping review aims to provide a holistic perspective on the influence of spaceflight and associated stressors—including gravitation (hyper- and microgravity), radiation, and vibration—on the potential for cancer development and altered cellular mechanisms. We adhered to the PRISMA-ScR checklist for our review. A multitiered search strategy was employed in English, starting with a preliminary keyword identification in Google Scholar and PubMed. Subsequently, the main search was conducted across five databases—Cochrane, Embase, PubMed, Scopus, and Web of Science—until 22 February 2024. All included studies were thoroughly assessed by two independent reviewers. Of the 15,553 identified articles, 158 were deemed eligible. The majority (92%) were experimental studies, predominantly cell-based (74.17%). Breast (15.19%), thyroid (13.92%), and hematopoietic (11.40%) cancers were the most frequently examined. Spaceflight stressors could affect different biological systems variably, with microgravity impacting spatial growth and metastasis, and cosmic radiation exerting both tumor-suppressive and mutagenic effects. Our findings highlight the need for large-scale, prolonged analog studies mimicking space conditions to enhance mission safety and shed light on the nuanced effects of space stressors on cancer. Additionally, further extensive studies need to be performed in the true weightlessness of spaceflight, both animal-based and on human tissue (cell cultures and potentially whole perfusion organ models), in addition to crew pre/intra/post-flight long-duration evaluations. Furthermore, this unique research avenue may reveal cancer cell sensitivities to these stressors, opening new pathways for innovative therapeutic strategies in cancer treatment.