Table 7 Summarizes the different types of approaches for the prevention, management and treatment of skin cancer; a) Physical approaches, b) Dermal chemotherapy, c) combination of physical therapy and chemotherapy (Physico-chemical combination therapy), d) Dug-Drug combination therapies, e) Herbal drugs for the skin cancer management, f) nanotechnological approaches for the drug delivery to the skin cancer
a: Physical methods used for the treatment of skin cancer | ||
Sr. No | Type of approach | Inference |
1 | Surgery | |
a. Simple excision | Areas associated with tumours are completely cut out and removed, along with some of the body's normal cells or tissues, after which the dermatopathologist sutures the wound | |
b. Mohs micrographic surgery | It is utilized more frequently for big area tumours, which combine the excision of tumorous tissue with microscopic analysis during the surgical procedure | |
c. Electrodessication and Curette (ED&C) | The health specialist uses a curette, an instrument with sharp edges and a small scoop, to remove the tumor after first numbing the area by applying local anesthetic. To stop any further bleeding, they use a probe that uses electricity or electric current | |
2 | Photodynamic therapy | When a specific wavelength of light is shone upon the affected area after a topical drug has been applied, the area becomes further stimulated. The impact of photochemical reactions on biological tissues is the key element of photodynamic therapy (PDT), a method of treating malignancies, including cancer. These processes' starter is light energy |
3 | Immunotherapy | Antigen–antibody interactions are the basis of the innovative cancer treatment method known as immunotherapy. Interferon is a key component of immunotherapy for the treatment of cancer and acts on target cells by tying up with receptors on those cells. Interferons have an antiproliferative effect on cancer cells and aid the immune system in combating substances that cause cancer |
4 | Targeted therapy | Targeted therapy drugs stop the growth of melanoma cells that have mutant serine/threonine-protein kinase B-Raf (BRAF), mitogen-activated protein kinase (MEK), or tyrosine-protein kinase Kit (C-KIT) genes. Only these mutant genes are subject to targeted therapy; however, not all melanoma cells carry these mutations |
5 | Chemical peel | Trichloroacetic acid (TCA) must be applied directly to malignant lesions during a chemical peel, which results in the top layer of skin being removed. It is mostly used for skin lesions that are precancerous |
6 | Radiotherapy | A successful and flexible non-surgical (or medical) method for tissue preservation is radiotherapy. For those for whom excision may not be viable (medically or technically inoperable) or may be seen as less ideal (e.g., cosmetic consequence), radiotherapy is an excellent alternative |
b: Dermal Chemotherapy Approaches for skin cancer treatment | ||
Sr. No | Type of approach | Inference |
Dermal Chemotherapy | ||
 1 | Topical chemotherapy | Dermal drug delivery is a general phrase used to describe the topical or transdermal application of dosage forms to the skin. In some cases, topical treatment may be more successful, particularly when the patient declines surgical intervention or when surgery is not an option |
a. 5- Fluorouracil (5-FU) | The pyrimidine analogue 5-FU is an antineoplastic antimetabolite that binds to thymidylate synthase with the help of the co-factor 5,10-methylene tetrahydrofolate. Inhibition of thymidine synthesis, impaired DNA replication, and consequent induction of apoptosis ensue from this. A typical topical treatment for superficial basal cell carcinoma (sBCC) is a 5% 5-FU cream or solution | |
 2 | Topical immunotherapy |  |
a. Imiquimod (IMQ) | Low-molecular-weight IMQ is a synthetic substance. It belongs to the imidazoquinolinone family. Off-label, nBCC uses 5% cream of IMQ. To combat sBCC, it is a permitted medication, though | |
 3 | Other drug therapies |  |
| Â | a. Retinoids | Retinoids can modify immunological response, keratinocyte differentiation, apoptosis, tumor cell proliferation, or a combination of these to exert their chemo-preventive effects. A clinical study that used the retinoic acid derivative tazarotene to treat BBCs proved successful. A clinical trial looked into the best way to treat sBCC or nBCC by applying 0.1% tazarotene gel once daily for up to 8Â months |
| Â | b. Ingenol mebutate (IM) | One of the materials recovered from the sap of the Euphorbia peplus plant is IM. By encouraging the production of anti-tumor antibodies and proinflammatory cytokines, IM promotes cellular cytotoxicity and inhibits recurrence. topical IM 0.05% gel in BCC, which characterizes the inflammatory response |
c: Physico-chemical Combination therapies | ||
Sr. No | Type of approach | Inference |
1 | Pembrolizumab + Postoperative radiotherapy | The study found no dose-related impact and a progression-free survival rate of 94.4%. 5.56% of the patients had some mild toxicities, such as anemia, rash, fever, edema, etc |
2 | liposomal gold nanoparticles encapsulating curcumin + Photothermal treatment | The absorption of gold nanoparticles with curcumin encapsulation was greatly enhanced. Because of the presence of curcumin, the group treated with curcumin gold nanoparticles shown increased cytotoxicity to cancer cells after laser irradiation |
3 | Titanium-dioxide-nanoparticle–gold-nanocluster–graphene + PDT | Treatment with TAG nanocomposites intravenously or intratumorally can significantly affect the clinical tumor tissue of mice with B16F1 tumor xenografts and decrease cancer progression |
4 | Photodynamic therapy (PDT) + Photothermal therapy (PTT) | Complete cell/tumor eradication has been observed in one as well as other in vivo as well as in vitro, suggesting that the combination PDT/PPTT activity generated by AuNRs/MoS2-ICG are substantially more effective than either one of synergistic PPTT or PDT alone |
5 | 5-FU loaded immunoliposome + Iontophoresis | In comparison to identical therapy utilizing control liposomes, the study showed that 5-FU penetration into viable epidermis by iontophoresis of immunoliposomes increased that penetration |
|  | Curcumin and Topotecan nanocapsules + Ultrasound | The effect on tumor growth was shown to be 3.5 and 14.8 times greater when ultrasound was employed in conjunction with this produced formulation as opposed to when ultrasound was not used and when only a physical mixing of medications was used, respectively |
d: Drug Combination therapy for the treatment of skin cancer | ||
Sr. No | Type of approach | Inference |
1 | Ipilimumab + Interleukin-2 (IL-2) | A higher percentage of complete responses, a sustained survival without cancer progression, or an improved response rate are all preferred outcomes |
2 | Iron oxide magnetic nanoparticles (NPs) + TLR agonists | The vaccines were more effective on B16F10 melanoma cells that were aggressive. Additionally, the researchers were able to track the vaccine's path from the injection site to the lymph nodes and tumor using magnetic resonance and nuclear imaging |
3 | Ipilimumab + T-VEC | When employed in combination, a 38.8% Objective Response Rate (ORR) was attained. However, when ipilimumab was administered alone, the ORR was just 18.0% |
4 | Toll-like receptor-9 (TLR9) + CMP-001 | By reducing the chronic inflammation brought on by systemic immunotherapies, TLR9 agonists may be used in combination therapies to combat immunological depletion and restrict metastases |
5 | Trametinib + Atezolizumab | Trametinib and atezolizumab together against BRAF-wild type melanoma demonstrated encouraging results in patients |
6 | Nivolumab + Ipilimumab | Nivolumab and ipilimumab in combination showed persistent, improved clinical outcomes than monotherapy in trial participants with advanced melanoma |
7 | 5-FU topical therapy + Cetuximab | enhanced efficiency of topical 5-FU treatment for SCC. After incubating with A431 cells for 120 h, cetuximab had a high cytotoxic effect, while immunoliposomes containing cetuximab and 5-FU indicated synergism |
8 | Rapamycin + PHT-427 | In comparison to vehicle controls, the combination led to a substantial decrease in tumor multiplicity. Combining topical Akt inhibitors (PHT-427) with mTOR inhibitors (rapamycin) may be a successful chemoprevention method for patients who have a high risk of developing cutaneous SCC |
e: Herbal drugs used for prevention and management of skin cancer | ||
Sr. No | Type of approach | Inference |
1 | Quercetin | Flavanol quercetin can be identified by the presence of -OH groups at positions 3, 5, 7, and 3' and 4' of the flavanol framework. The main contributors to quercetin's anti-cancer effect are its anti-oxidant and anti-inflammatory capabilities. In murine melanoma cells (B16-BL6), quercetin decreased Bcl-2 expression and activity and increased the activity and potential of caspase-3, which caused the cells to die |
2 | Kaempferol | Kaempferol-rich meals have been linked to a lower incidence of pancreatic, gastric, lung, ovarian, and other cancers as well as cardiovascular disease. Kaempferol has been shown to disrupt the choroidal melanoma cell cycle's G2/M phase |
3 | Epigallocatechin-3-gallate | The primary sources of epigallocatechin-3-gallate (EGCG), also known as flavan-3-ols, are tea, red wine, strawberry, and cocoa goods. EGCG can stop the cell cycle and induce apoptosis in melanoma cells (A374 and Hs-294Â T). It can have a number of effects, such as the induction of tumor-suppressor proteins (p16INK4a, p21WAF1/CIP1, and p2KP1), upregulation of the pro-apoptosis protein Bcl-2 associated X protein (Bax), activation of caspases-3, -7, and -9, and downregulation of proteins that inhibit apoptosis or promote cell survival |
4 | Apigenin | The flavonoid apigenin, also known chemically as 4',5,7, -trihydroxy flavone, is thought to prevent UV-induced skin cancer by triggering the AMPK pathway (AMP-activated protein kinase), which in turn suppresses baseline mTOR activity in keratinocytes grown in vitro |
5 | Daidzein | Daidzein, commonly known as soy isoflavone, was thought to have anticancer properties by preventing CDK2 (Cyclin dependent kinase) from activating during the G1 phase of the cell cycle |
6 | β-Carotene | Carrots, kale, pepper, spinach, pumpkin, sweet potatoes, and cantaloupe are some of the main sources. The inhibition of Bcl-2, p53, and caspase-3 in murine melanoma cells may be the mode of action of -carotene, which subsequently induces apoptosis and potency of -carotene upon tumour specific angiogenesis, which affects tumor growth |
7 | Resveratrol | Resveratrol, a naturally occurring group-A stilbene phytoalexin antioxidant, has been demonstrated to inhibit the lipopolysaccharide-induced epithelial to mesenchymal transition, most likely by modulating NF-B signaling as a result of its anti-metastatic effects |
8 | Curcumin | Curcumin's ability to inhibit tumor growth is aided by three distinct mechanisms: (i) Upregulation of tumor suppressor genes (like p53) and downregulation of anti-apoptotic proteins causes apoptosis to be induced in tumor cells. (ii) Matrix metalloproteinase (MMP) downregulation, which inhibits tumor invasion; and (iii) the anti-inflammatory action, which boosts its effectiveness against tumors |
9 | Sulforaphane | It can be found in cruciferous vegetables like cauliflower, radish, cabbage, and broccoli. It has been shown that sulforaphane possesses anticancer properties, including the potential to cause apoptosis, limit cell proliferation, and stop metastasis. Sulforaphane induces apoptosis by triggering the p53 protein, caspase 3, caspase 9, the Bax gene, and caspase 9 |
10 | Hypericum perforatum | John's Wort, often known as St. Hypericum perforatum, is a penanthroperylene quinine with photosensitive properties. Due to its concentration and low dosage dependent photo-sensitizing properties, Hypericin is an excellent candidate to be employed in photodynamic therapy for skin cancer. In melanoma, the UVA activated hypericin produced cell demising by the necrosis and apoptosis pathways |
11 | Withania somnifera | Due to Withaferin A's capacity to down regulate Bcl-2 and trigger the generation of Reactive Oxygen Species (ROS), Withania Somnifera, also known as Ashwagandha or Indian ginseng, causes Melanoma cells to undergo apoptosis when administered alone |
12 | Melaleuca alternifolia | It is also known as tea tree oil, terpinen-4-ol, or tea tree oil, and studies in vitro have shown that it can slow the growth of melanoma cells by inducing apoptosis, cell cycle arrest, necrosis, and preventing cell proliferation at low dosages while being safe for normal fibroblast cells |
13 | Rosmarinus officinalis | The main component in R. officinalis extract is carnosol, a phenolic diterpene. Carnosol prevented metastatic murine melanoma cells from migrating into the basement membrane, and this result was linked to the suppression of MMP-9 |
14 | Aloe Species | Emodin exhibits an anti-proliferation impact that is time-dependent and can stop MMP-9's anti-melanoma action. Aloe-emodin treatment has anti-metastatic effects by inhibiting murine melanoma cell adhesion, invasion, migration, and aggregation |
15 | Ingenol Mebutate | It is a modulator of eight PKC (Protein Kinase C isoenzyme) isoforms that are involved in signaling pathways such as cell angiogenesis, invasion, survival/cell death (survival/autophagy), and cell proliferation. It also functions as either a tumor suppressor or an oncogene |
16 | Zingiber officinale | The p38 MAP kinase-NF-B signaling pathway was normally blocked to prevent TPA's induction of COX-2 in mice, which is what caused the anticancer activity |
17 | Cannabinoids | In melanoma cells, the phytocannabinoid D9- Tetrahydrocannabinol (THC) induces autophagy, leads to apoptosis, and reduces cell viability. These effects were strengthened by the addition of cannabidiol, and they were demonstrated in a mouse model of melanoma with xenografts |
18 | Retinoids | The nucleic receptor (NR) of the Retinoic Acid Receptors (RAR) subfamily, including as RAR, RAR, and RAR, is where retinoids are expected to work |
f: Nanotechnological approaches to tackle skin cancer | ||
Sr. No | Type | Inference |
1 | Nano-biosensors | Indicators of skin diseases are frequently identified using biosensor or nano-biosensor technologies. Nano-sensors are employed as a perceptual aid in the physical evidence of a living creature. Building immunosensors that are beneficial for cancer diagnosis requires the use of antibodies that are electrochemically transducer-anchored |
2 | Quantum Dots | These are nanocrystals with colloidal fluorescent semiconductors that range in size from 2 to 10Â nm. Etoposide and methotrexate were grafted onto Fe3O4-Ag2O quantum dots that were adorned on cellulose fibers. These created Fe3O4-Ag2O quantum dots displayed ferromagnetic properties and released etoposide and methotrexate at rates of 78.94% and 63.84%, respectively |
3 | Nanotubes | Coaxial graphite sheets are twisted into cylindrical or barrel shapes to form carbon nanotubes, a type of fullerene. By measuring cell survival, free radical generation, and the buildup of metabolites associated with peroxide, researchers were able to explore the impact of extended single-wall carbon nanotube (SWCNT) exposure on cellular toxicity and oxidative stress |
4 | Iron Oxide Nanoparticles | Because of its improved drug encapsulating capacity, strong magnetic responsiveness, and improved targeted delivery efficiency, the superparamagnetic iron-oxide NPs (SPION) have been investigated for drug targeting and other biological applications |
5 | Gold nanoparticle | Gold nanoparticles (AuNPs) are the most commonly used and highly accepted platforms for identifying, treating, and monitoring skin conditions, including skin cancer |
6 | Titanium Dioxide | They serve as inorganic physical sun blockers in sunscreens and help stop skin cancer from being brought on by exposure to the sun. The potential for antitumor properties in photocatalyzed TiO2 nanoparticles makes them especially intriguing for use in traditional anticancer therapies |
7 | Zinc Oxide Nanoparticle | By enhancing both mitotic (related to cytogenetic damage) and interphase (apoptosis) death, the application of ZnO nanoparticles sensitizes tumor cells. Studies show that melanoma cancer cells' intracellular ROS production significantly increases after being treated with different doses of ZnO nanoparticles, indicating that ZnO nanoparticles may be employed in a range of skin-related applications |
8 | Cerium Oxide Nanoparticle | Cerium oxide nanoparticles (CNPs) are a relatively new approach to treating cancer. They are suitable for radiation therapy because of their "smart" ability to selectively trigger cellular apoptosis in radio-exposed cancer cells |
9 | Silver Nanoparticle | AgNPs' cytotoxicity is influenced by their surface charge and size. Smaller particles pose a greater threat because of their greater surface area |
10 | Polymeric Nano-micelles | Drugs have been applied to the skin using nano-micelles. polymer-based nano-carriers for siRNA delivery to the skin in order to treat melanoma. The ability of encapsulated siRNA to stop skin cancer from spreading is replicated. This study shows that cationic micelles are efficient gene delivery nanoplatforms for melanoma therapy |
11 | Polymeric Nanoparticles | Due to their improved stability, controlled release, and capacity to permeate the skin through a polymeric matrix, polymeric nanoparticles are crucial when applied to the skin. Cancer cell membrane coated nanoparticles (CCM-CMSN), which also have an extended circulation half-life and outstanding biocompatibility, offer excellent cancer targeting abilities |
12 | Lipid Nanoparticle | The most biocompatible nanoparticles studied for skin application are lipid nanoparticles, it has been found. Lipid formulation is said to have the ability to penetrate the skin and deliver the medication deeper into its layers |
13 | Nano-emulsions | Nano emulsions are dependable systems with distinct rheological traits and a transparent appearance. By keeping skin moisture in place and being more permeable to APIs, nano-emulsions have an advantage over other types of emulsions in reducing trans epidermal water loss (TEWL) |
14 | Liposomes | Small, double-layered phospholipid vesicles called liposomes, which resemble biological membranes in their inner hydrophilic core, are composed of phospholipids. When administered intravenously, unique PEGylated liposomes are designed to pass through the reticuloendothelial system (RES), reducing the rate at which the active pharmaceutical molecule is cleared and lengthening the circulation half-life |
15 | Dendrimers | Dendrimers are synthetic monodisperse, unimolecular polymers with a size of less than 15Â nm. Several literature sources demonstrate the capability of dendrimer targeting ligands to cause the precise targeting and eradication of tumors. In addition to oligosaccharides, polysaccharides, oligopeptides, and polyunsaturated fatty acids, they also contain folate and cancer associated antigen |
16 | Magnetic Nanoparticle | By using electron microscopy, it was discovered that this particle only showed up in melanoma cells. When a 43 °C external alternating magnetic field was utilized to heat up the tumor, it was found that melanoma cells started to break down |
17 | Nanostructured lipid carriers | NLCs are a superior alternative to Solid-lipid nanoparticles (SLNs) for topical preparation due to several advantages associated with the use of biodegradable lipids, which guarantee low cytotoxicity and systemic toxicity. Due to the presence of solid lipid in it, small NLC particles may promote the intimate contact of the formulation with the stratum corneum, enhancing the drug's ability to pass through the skin. They may also enhance the controlled release of API from the carriers |