Solasodine, Solamargine and Mixtures of Solasodine Rhamnosides: Pathway to Expansive Clinical Anticancer Therapies

Cancer remains a major cause of mortality worldwide. Progresses have been made in the understanding of the molecular basis of cancer, cancer detection, and cancer treatment. Important strides by treating early-stage cancers have resulted in improved outcomes. Despite these achievements, mortality of cancer patients is high and still there is no cure. Some oncologists remain optimistic that cytotoxic chemotherapy will significantly improve cancer survival. However, notwithstanding the use of new and expensive single and more recently, combination drugs, the improvement of the response rates remains very low. In the United States, cancer death rates decreased by a mere 1.4% to 1.8% from 2004 to 2013. Compared to other serious diseases, the improvement of the cancer patient has been disappointingly lagging, and by far, most patients with advanced cancer eventually die of their disease. The need for improved cancer therapies is self-evident. This communication gives an overview of the overwhelming resurgence of solasodine and its glycosides in cancer therapy.

Drug therapy: Solamargine and other solasodine rhamnosyl glycosides as anticancer agents

In the last century, the discovery of cytotoxic agents was revolutionary for anticancer therapy. These therapies have resulted in better understanding of cancer in general. However, the development of agents that combine efficacy, safety and convenience remains a great challenge. The narrow, if not adverse, therapeutic index of most drugs, the damage not only to cancer cells, but also to normal and healthy tissue and the occurrence of resistance have limited anticancer efficacy. This review presents the development of promising novel cytotoxic solasodine rhamnosyl glycoside drugs that offer not only gains in specificity and efficacy, but also in safety, tolerability, non-resistance and convenience in the treatment of patients with cancer.

The Value of Excipients and the Required Understanding of the Biological System in Product Development: An Impactful Example of Curaderm, a Topical Skin Cancer Treatment

The incidences of nonmelanoma skin cancer are increasing worldwide, and the ongoing war on its treatment necessitates the development of effective and non-invasive methods. Through basic and clinical research, non-invasive treatments like Curaderm have been developed, leading to improved quality of life for patients. Excipients, previously considered inactive ingredients, play a crucial role in enhancing the performance of topical formulations. The development of Curaderm emphasizes the importance of understanding the interactions between active ingredients, excipients, and the biological system to create effective and affordable pharmaceutical formulations. The systematic approach taken in the development of Curaderm, starting from the observation of the anticancer activity of natural solasodine glycosides and progressing through toxicological and efficacy studies in cell culture, animals, and humans, has provided insights into the pharmacokinetics and pharmacodynamics of solasodine glycosides. It is crucial to determine these pharmacological parameters within the skin’s biological system for maximal effectiveness and cost-effectiveness of a skin cancer treatment. Curaderm, as a topical treatment for nonmelanoma skin cancer, offers benefits beyond those obtained from other topical treatments, providing hope for improved quality of life for patients.

Induction of actin disruption and downregulation of P-glycoprotein expression by solamargine in multidrug-resistant K562/A02 cells

Background Solamargine （SM）, a steroidal glycoalkaloid isolated from the Chinese herb Solanum incanum, has been shown to inhibit the growth of some cancer cell lines and induce significant apoptosis. However, the effects of SM on multidrug-resistant （MDR） cells and the molecular mechanisms involved are poorly understood. The purpose of this study was to evaluate the anti-MDR effects of SM and the associated mechanisms in MDR K562/A02 cells. Methods The cytotoxicity of SM was measured by 3-（4,5-dimethylthiazol）-2,5-diphenyltetrazolium bromide （MTT） assay. The 14＇,6-diamidino-2-phenylindole （DAPi） nuclear staining and flow cytometry were used to detect SM-induced apoptosis. The mRNA expression of P-glycoprotein （P-gp） was investigated by real-time PCR （RT-PCR）. Western blotting was used to determine the expression of Bcl-2, Bax, and actin. The changes in the morphology of actin were examined with immunofluorescence staining. Results MTT results showed that SM effectively killed the MDR sublines K562/A02, KB/VCR, and H460/paclitaxel （Taxol）, and their parental cell lines K562, KB, and H460 to an equivalent or more sensitive degree. Based on the results by flow cytometry and immunostaining, the pro-apoptotic effects of SM were observed in MDR K562/A02 cells. Furthermore, the RT-PCR results showed that SM induced the downregulation of MDR1 mRNA. In addition, the expression of P-gp and actin was decreased in the SM-treated cells, as measured by western blotting and immunostaining. Conclusions These results demonstrate that SM effectively triggers apoptosis in MDR tumor cells, which is associated with actin disruption and downregulation of MDR1 expression. This compound may merit further investigation as a Potential therapeutic aaent that bvDasses the MDR mechanism for the treatment of MDR tumors.

An alternative total synthesis of solamargine

Solamargine, （25R）-3β-（O-a-L-rhamnopyranosyl-（1--2）-[O-a-L-rhamnopyranosyl-（1--4）]-β-D-glucopyranosloxy}-22a-N- spirosol-5-ene, isolated from the berries of solanum aculeastrum, has been synthesized in 26.8% overall yield. First glycosylation before N-cyclization significantly facilitated synthesis of the desired molecule. We anticipate that this work will provide a new approach to access solamargine and its diversified analogues.

Modification of Sugar Chains in Glycoalkaloids and Variation of Anticancer Activity

To study the effect of the sugar chains in glycoalkaloids against cancer cells, 6-0-sulfated solamargine and acidcatalyzed hydrolytic products of α-solamargine and α-solasonine were prepared. The sulfation at 0-6 of solamargine was proceeded in five steps. The 6-OH group was first selectively protected with DMT-Cl, and then the secondary hydroxyl groups on the sugar ring were acetylated. After the protective group DMTr was removed, the free 6-OH group was sulfated. Finally, the acetyl groups were removed to give 6-0-sulfated solamargine in a good yield. The hydrolyses of solamargine and solasonine were performed in diluted hydrogen chlorede. Three and two hydrolyzed products were obtained from solamargine and solasonine, respectively. The antiproliferative activities against HCT-8 tumor cells of two glycoalkaloids and their derivaties were examined via a MTT assay. The results show that α-solamargine and α-solasonine exhibit strong cytotoxic activities with an IC50 of 10. 63 and 11.97 μmol/L, respectively, wheras their derivaties seem to be less activities.

Intralesion and Curaderm^BEC5Topical Combination Therapies of Solasodine Rhamnosyl Glycosides Derived from the Eggplant or Devil’s Apple Result in Rapid Removal of Large Skin Cancers. Methods of Treatment Compared

Solasodine rhamnosyl glycosides (SRGs) are chemotherapeutic agents for the treatment of cancer. SRGs in a cream formulation, CuradermBEC5, is very effective for the treatment of nonmelanoma skin cancers with excellent cosmetic end results. Intralesion injection of SRGs successfully dispose of very large tumours in animals without any clinical adverse effects. The mode of action of SRGs is by apoptosis. In this study, it is shown that small to large basal cell carcinomas are effectively treated only with topical application of CuradermBEC5. Here it is reported for the first time that combination of intralesion SRG injection and topical application with CuradermBEC5 in humans reduces the treatment time period by more than half when compared with topical application as the sole treatment regime. Two intralesion injections of very low doses of SRGs rapidly and effectively remove a large melanoma on a horse. If rapid removal of large troublesome skin cancers is required then this can be achieved by intralesion and topical treatments. Intralesion or combination therapy with SRGs may have some applications for melanomas in situ such as lentigo maligna.

Solasodine Glycosides: A Topical Therapy for Actinic Keratosis. A Single-Blind, Randomized, Placebo-Controlled, Parallel Group Study with Curaderm^BEC5

Background: Untreated actinic keratosis can advance to squamous cell carcinoma, which in turn is associated with a risk of metastasis. Current treatments for actinic keratosis have many shortcomings. This communication describes the efficacy and safety of a topical cream therapy, CuradermBEC5, containing solasodine glycosides (0.005%) for actinic keratosis.Methods: Randomly assigned patients with actinic keratosis on the face, trunk or extremities received so-lasodine glycosides cream (CuradermBEC5) or placebo (vehicle) that was self-applied to the lesions and covered with an occlusive dressing (micropore) twice daily for 3 consecutive days. Complete clearance and local reactions were as-sessed at 56 days with follow-up periods of 6 months and 1 year. Results: The rate of complete clearance at day 56 was higher with solasodine glycosides than with placebo (92% vs. 38%, P 0.001). The absolute success rates after 1 year follow-up were 82% for solasodine glycosides and 18% for placebo. No differences in local reactions were obtained when solasodine glycosides and placebo were compared. Local reactions in both groups peaked at days 2 and 3 with local pain as the major event. The pain associated with treatments lasted approximately 10 minutes after application of solasodine glycosides and placebo. Complete reepithelialization occurred two weeks after treatment. Adverse events were generally mild to moderate in intensity and resolved without sequelae. Conclusions: Solasodine glycosides cream applied topically twice daily with a dressing for 3 days is effective for the treatment of actinic keratoses.

Combination Treatment with BEC and Cisplatin Synergistically Augments Anticancer Activity and Results in Increased Absolute Survival

Plant-derived BEC with its main component solamargine possesses anticancer activities via its effect on a variety of biological pathways in a wide range of human cancer cells. High cure rates with BEC therapy have been obtained in animals with deadly cancers, and, in humans with terminal cancers promising results have been reported. At a clinical level, optimal concentrations of BEC have been established in a topical cream formulation Curaderm, for effective removal of skin cancers, but optimal concentrations of BEC have not been reported for other cancers. The objective of this study was to determine whether combination therapy of Cisplatin with BEC would result in synergism using cure rates as end points. BEC on its own cures Sarcoma 180 in mice, whereas, Cisplatin on its own has no effect on Sarcoma 180 activity. A combination of BEC and Cisplatin shows synergism, resulting in higher cure rates than BEC and Cisplatin at comparable individual concentrations.

Topical Solasodine Rhamnosyl Glycosides Derived From the Eggplant Treats Large Skin Cancers: Two Case Reports

Solasodine rhamnosyl glycosides (BEC) are a new class of antineoplastics that show superior efficacy than many established anticancer drugs as shown by intravenous, intraperitoneal and intralesion administrations. Previous studies have described the efficacy of BEC on nonmelanoma skin cancers by topical application. Two cases are now reported which show that BEC in a cream formulation Curaderm is very effective for the treatment of large nonmelanoma skin cancers that are considered difficult to treat by existing modalities. Moreover, the cosmetic outcomes are very impressive.

First in Man Topical Treatment of Melanoma with Solasodine Glycosides in a Formulation Curaderm: A Case Report

Background: There is ample evidence to support the safety and efficacy of the topical anticancer cream Curaderm in the treatment of non-melanoma skin cancers. Curaderm contains the natural glycoalkaloid solamargine in the form of BEC, which has been established as a novel antineoplastic agent. BEC is the initials of the inventor of the described technology. It is known that BEC expresses anti-melanoma properties in cell culture and animals. Because of potential metastasis, clinical work with BEC on melanoma was stalled. However, recent studies show that BEC has anti-metastatic properties and this, together with currently better understanding of the mode of anti-cancer actions of BEC, has led to the treatment of a patient who refused to have surgery for her clinically diagnosed stage II melanoma. Treatment: A 67-year woman had a birthmark that developed into a clinically diagnosed stage II melanoma and was treated with topical application of Curaderm twice daily for 7 weeks. Results: The pattern of response of the melanoma to Curaderm therapy was similar to that observed when basal cell carcinoma is treated with Curaderm. The melanoma responded rapidly to the treatment and in 7 weeks the lesion was removed with no demonstrable side effects. The cosmetic end result was very acceptable. Conclusion: The clinical resolution of the melanoma with Curaderm pharmacotherapy conforms to the cell culture and animal observations that solasodine rhamnosides, and thus Curaderm, is very specific and efficacious for the first in man treatment of melanoma, creating the possibility of a simple treatment for melanoma. Further investigations with controlled clinical trials are warranted.

Curaderm, the Long-Awaited Breakthrough for Basal Cell Carcinoma

Background: Basal cells form a continuous cell layer at the bottom of the epidermis, which is the outermost layer of the skin. Basal cell carcinoma occurs when a mutation occurs in the DNA of a basal cell. The mutation inhibits apoptosis—the programmed cell death mechanism. The cell continues to multiply but does not die, resulting in a change in the skin, such as a growth or sore that will not heal. Basal cell carcinoma is the most common form of skin cancer and the most frequently occurring form of all cancers. Key words searched for the database of this communication were: Curaderm, BEC 5, cancer, skin cancer, basal cell carcinoma, nonmelanoma skin cancer, solamargine, solasonine and solasodine glycosides. Treatments: Several types of treatments are available to remove or destroy basal cell carcinoma. All currently used treatments are indiscriminate and also remove or destroy normal skin cells resulting in compromised cosmetic outcomes. Development of Curaderm Pharmacotherapy: Curaderm pharmacotherapy discriminates and specifically activates apoptosis at the molecular level in cancer cells but not in normal cells. Accordingly, Curaderm pharmacotherapy for basal cell carcinoma effectively and safely treats virtually all types, sizes and lesion locations. This review describes studies from the inception of Curaderm pharmacotherapy and covers the discovery of the anti-cancer effects, mode of action, preclinical, clinical and field applications with emphasis on efficacy, safety, compliance, tolerance, cost effectiveness and especially cosmetic outcome. In 2018 Curaderm was approved by the European Health Authorities as a Medical Device Class 1 for the indication “Topical Treatment with Keratolytic Action, and Antineoplastic Activity in the Treatment and Healing of Localized Basal Cell Carcinoma of the Skin”.

Treatment of Skin Cancer with a Selective Apoptotic-Inducing Curaderm^BEC5Topical Cream Containing Solasodine Rhamnosides

Solasodine rhamnosides produced in plants as secondary metabolites, are safe and effective when treating a variety of cancers, including non-melanoma skin cancers. They are cytotoxic against multi-drug resistant tumor cells, stimulate lasting immunity against cancer, are not mutagenic and display anti-mutagenic properties. These antineoplastics, through cellular specific receptor-mediated actions, directly induce apoptosis by triggering extrinsic and intrinsic apoptotic pathways in cancer cells but not normal cells. CuradermBEC5 contains solasodine rhamnosides and is a topical formulation for the treatment of keratoses and non-melanoma skin cancers. The mode of action, together with the selectivity towards cancer cells, with CuradermBEC5 therapy, results in outstanding beneficial outcomes. This study shows graphically and pictorially that CuradermBEC5 seeks and destroys basal cell carcinoma whilst normal skin cells replace the dead cancer cells during therapy, emanating into impressive cosmetic end results. The clinical observations with CuradermBEC5 therapy reveal that initially the lesion size increases over four-fold due to the interaction of CuradermBEC5 with deeper and more lateral tumor cells, followed by a decrease in size, ultimately, resulting in complete elimination of the basal cell carcinoma.

Topical Curaderm^BEC5Therapy for Periocular Nonmela-noma Skin Cancers: A Review of Clinical Outcomes

Approximately 5 to 10 percent of all skin cancers occur in the periocular region. Basal cell carcinoma is the most frequent malignant periocular tumor, followed by squamous cell carcinoma, sebaceous gland carcinoma, and malignant melanoma. Nonmelanoma skin tumors at the periocular area often cause disfigurement with destruction of soft conjunctival tissue. Many therapeutic methods have been recommended to combat the morbidity and mortality associated with these lesions. Excisions with frozen-section control or Mohs micrographic surgery are regarded as the gold-standard treatments for periocular basal cell and squamous cell carcinomas. However, these treatment modalities have various limitations and reconstruction surgery is often associated with these treatment options. The chemotherapeutic agents solasodine rhamnosides in a cream formulation CuradermBEC5 are specific, effective and safe treatments for nonmelanoma skin cancers with excellent cosmesis. The antineoplastic mode of action is by apoptosis. In this review it is shown that CuradermBEC5 also treats periocular basal cell carcinoma and squamous cell carcinoma with impressive cosmetic outcomes and no reconstructive surgery is required.

Curaderm^BEC5for Skin Cancers, Is It? An Overview

Skin cancer incidence is increasing at alarming rates and is considered by some as an epidemic. Its incidence is higher than all other cancers combined. The developments of new treatments have not parallelled the increased incidences of this disease. A variety of treatments are available with differing outcomes. More recently a novel topical treatment, consisting of the antineoplastic compounds solasodine rhamnosyl glycosides, solamargine and solasonine, which are derived from plant material, has been described that claims to have many advantages over the currently used skin cancer therapies. This review investigates such claims.

Evaluation of Dermal Irritation and Skin Sensitization by Curaderm

Purpose: To establish whether Curaderm, a topical pharmacotherapy for skin cancer, irritates or sensitizes normal skin. Methods: The dermal irritation and skin sensitization toxicity of Curaderm were investigated in rabbits and guinea pigs in compliance with the Organization for Economic Cooperation and Development guideline. To assess dermal irritation, rabbits were dermally exposed to Curaderm for varying periods of time. To assess hypersensitivity, the guinea-pig maximisation test was applied. Results: Curaderm was only negligibly irritating using the criteria of erythema and oedema. Curaderm did not produce any sensitization toxicity of the skin. Conclusion: These studies confirm the non-toxic observations on normal skin experienced in the clinical setting when treating skin cancer and reinforce the specificity of Curaderm towards cancer cells.