Cantharidin-Podophyllin-Salicylic Acid Formulation as a First-Line Treatment for Plantar Warts? A Case Report with Multiple Plantar Warts of Human Papillomavirus Biotype 27 and Previous Failed Treatments.

BACKGROUND Plantar warts are benign skin tumors caused by the human papillomavirus (HPV). There are multiple treatments, but none ensure absolute success. Successful treatment depends on several factors, such as the location, number of lesions, HPV biotype, and the patient's health condition. This report presents a 53-year-old woman who had multiple recalcitrant plantar warts with HPV biotype 27 that were treated using a cantharidin-podophyllin-salicylic acid (CPS) formulation after 2 failed treatments. CASE REPORT A 53-year-old woman was seen on October 25, 2021. She had 6 plantar warts due to HPV biotype 27, which was confirmed by polymerase chain reaction using a sample of hyperkeratosis scales obtained from the wart after debridement. Five cryotherapy sessions were applied, without clinical improvement. Two sessions of nitric-acid-zinc complex were then applied, from which the patient reported severe pain, without clinical improvement. Finally, 3 sessions of CPS formulation were applied, and the HPV remitted in all warts. CONCLUSIONS Conservative treatments, such as cryotherapy, have not been effective in a case of multiple recalcitrant plantar warts. The combined action of the 3 compounds of CPS formulation was key in the resolution of this case. Plantar wart treatment should be easy to apply, effective, fast, and efficient. In cases of recalcitrant or numerous warts, treatment should be more aggressive from the beginning if the patient's lifestyle allows it. It would be interesting to conduct randomized clinical trials to find out which patients could be indicated for the CPS formulation as a first line of treatment.

Treatment of recalcitrant plantar warts with long-pulsed Nd:YAG laser versus cantharidin-podophylline resin-salicylic acid.

BACKGROUND: Treatment for recalcitrant plantar warts remains a continuing challenge as the options for treatment have differing levels of success. long-pulsed Nd:YAG laser is considered a good treatment modality in resistant plantar warts. On the other hand, high cure rates have been reported with a topical proprietary formulation consisting of 1% cantharidin, 5% podophyllotoxin, 30% salicylic acid. AIM: To compare the efficacy of 1% cantharidin, 20% podophylline resin and 30% salicylic acid (CPS) versus long-pulsed Nd:YAG laser in the treatment of recalcitrant plantar warts. METHODS: This study included 30 patients with single or multiple recalcitrant plantar warts; patients were assigned to two groups: the first group included 15 patients with 71 recalcitrant plantar warts who were treated by long-pulsed Nd:YAG laser (group I) and the second group included 15 patients with 78 recalcitrant plantar warts who received CPS (group II). The diagnosis of plantar warts was made by clinical examination. RESULTS: Fourteen patients (93%) were completely cleared of their warts with topical CPS, while 11 patients (73%) showed complete clearance with long-pulsed Nd:YAG laser with statistically significant difference between the two groups. CONCLUSION: Topical CPS is safe and efficacious and represents a promising therapeutic modality than long-pulsed Nd:YAG laser in the treatment of recalcitrant plantar warts.

Medium throughput biochemical compound screening identifies novel agents for pharmacotherapy of neurofibromatosis type 1.

The variable manifestation of phenotypes that occur in patients with neurofibromatosis type 1 (NF1) includes benign and malignant neurocutaneous tumors for which no adequate treatment exists. Cell-based screening of known bioactive compounds library identified the protein phosphatase 2A (PP2A) inhibitor Cantharidin and the L-type calcium channel blocker Nifedipine as potential candidates for NF1 pharmacotherapy. Validation of screening results using human NF1-associated malignant peripheral nerve sheath tumor (MPNST) cells showed that Cantharidin effectively impeded MPNST cell growth, while Nifedipine treatment significantly decreased local tumor growth in an MPNST xenograft animal model. These data suggest that inhibitors of PP2A, as well as calcium channel blockers, might be used in broader MPNST preclinical studies as single agents or in combinatorial therapeutic strategies.

Anticancer effects of cantharidin in A431 human skin cancer (Epidermoid carcinoma) cells in vitro and in vivo.

Cantharidin (CTD), a potential anticancer agent of Traditional Chinese Medicine has cytotxic effects in different human cancer cell lines. The cytotoxic effects of CTD on A431 human skin cancer (epidermoid carcinoma) cells in vitro and in A431 cell xenograft mouse model were examined. In vitro, A431 human skin cell were treated with CTD for 24 and 48 h. Cell phase distribution, ROS production, Ca2+ release, Caspase activity and the level of apoptosis associated proteins were measured. In vivo, A431 cell xenograft mouse model were examined. CTD-induced cell morphological changes and decreased percentage of viable A431 cells via G0/G1 phase arrest and induced apoptosis. CTD-induced G0/G1 phase arrest through the reduction of protein levels of cyclin E, CDK6, and cyclin D in A431 cells. CTD-induced cell apoptosis of A431 cells also was confirm by DNA gel electrophoresis showed CTD-induced DNA fragmentation. CTD reduced the mitochondrial membrane potential and stimulated release of cytochrome c, AIF and Endo G in A431 cells. Flow cytometry demonstrated that CTD increased activity of caspase-8, -9 and -3. However, when cells were pretreated with specific caspase inhibitors activity was reduced and cell viability increased. CTD increased protein levels of death receptors such as DR4, DR5, TRAIL and levels of the active form of caspase-8, -9 and -3 in A431 cells. AIF and Endo G proteins levels were also enhanced by CTD. In vivo studies showed that CTD significantly inhibited A431 cell xenograft tumors in mice. Taken together, these in vitro and in vivo results provide insight into the mechanisms of CTD on cell growth and tumor production. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 723-738, 2017.

Clinical study on safety of cantharidin sodium and shenmai injection combined with chemotherapy in treating patients with breast cancer postoperatively.

OBJECTIVES: To assess side effects on Cantharidin sodium and Shenmai injection combined with chemotherapy in treating patients with breast cancer postoperatively. METHOD: Patients with breast cancer receiving postoperative chemotherapy were retrospectively collected, and divided into four groups: group A with cantharidin sodium injection combined with chemotherapy; group B with Shenmai injection combined with chemotherapy; group C with both cantharidin sodium and Shenmai injection combined with chemotherapy; while group D (control group) received chemotherapy alone. All patients were administered docetaxel at a dose of 75 mg/m2 on day 1, epirubicin hydrochloride at a dose of 60 mg/m2 on day 1, and cyclophosphamide at a dose of 500 mg/m2 on day 1 for 3 cycles (repeated at 21 day intervals). After ≥ three courses of treatment, quality of life and side effects were evaluated. RESULTS: There were a total of 78 patients in this study, and the incidence of leukopenia and gastrointestinal reactions in groups A and B were lower than those in the control group and lowest in group C (p<0.05). CONCLUSIONS: Thus cantharidin sodium and Shenmai injection combined with chemotherapy reduce side effects and deserve to be further investigated in randomized clinical control trials.

Effect of cantharidins in chemotherapy for hepatoma: a retrospective cohort study.

This study aimed to evaluate the effects of cantharidins, a traditional Chinese medicine, in chemotherapy for the treatment of hepatoma. From August 2011 to December 2012, 96 patients with hepatoma, who were eligible for transcatheter hepatic arterial chemoembolization and received cantharidins, were selected for comparison with the control group of 95 patients without cantharidins. The treatment effect, clinical symptoms and adverse effects were analyzed. The results of the study showed that the cantharidins group had a higher overall efficient rate than the control group (p < 0.001). The improvement rate of the Karnofsky score in the cantharidins group was significantly higher than that of the control group (p = 0.014). In the cantharidins group, there was a decrease in white blood cell (WBC) count and gastrointestinal response rates were lower than those of the control group (p < 0.05). Therefore, the traditional Chinese medicine cantharidins showed effects of easing the progress of liver cancer, relieving side effects of chemotherapy and improving the quality of life in the treatment of hepatoma.

Experimental study on the inhibitory effect of sodium cantharidinate on human hepatoma HepG2 cells.

BACKGROUND: [corrected] Cantharidin, and its derivatives can not only inhibit the proliferation of tumor cells, but can also induce tumor cell apoptosis. It shows cantharidin exhibits a wide range of reactivity in anticancer. The objective of this paper was to study the inhibitory effect of sodium cantharidinate on human hepatoma HepG2 cells. MATERIALS AND METHODS: MTT assay was used to detect the proliferation of HepG2 cells, and immunohisto-chemical method was used to detect the change in VEGF, protein level, and to determine the inhibitory effect of sodium cantharidinate on human hepatoma HepG2 cells. RESULTS: As results, sodium cantharidinate significantly inhibited the growth of HepG2 cells in a time-and dose-dependent manner. CONCLUSION: We conclude that sodium cantharidinate has an inhibitory effect on human hepatoma HepG2 cells.

Cantharidin-mediated ultrastructural and biochemical changes in mitochondria lead to apoptosis and necrosis in murine Dalton's lymphoma.

Cantharidin, a type of terpenoid, is the blistering agent of blister beetles frequently used in traditional medicine. The isolation and anticancer activity of cantharidin from blister beetles, Mylabris cichorii has been recently reported by us. This study deals with changes in mitochondrial structure and function and understanding their significance in the underlying mechanism(s) in cantharidin-mediated antitumor effects in Dalton's lymphoma (DL) bearing mice. Cantharidin treatment caused the appearance of abnormal mitochondrial features which included roundish mitochondria with thickened membranes, irregularity in cristae, and appearance of small and large size vacuoles in mitochondria of DL cells. Cantharidin treatment resulted in a decrease in mitochondrial reduced glutathione, succinate dehydrogenase activity, mitochondrial membrane potential, and induced apoptosis and necrosis in DL cells. The decrease/release of mitochondrial cytochrome c were also observed after cantharidin treatment. Flow cytometry-based cell cycle analysis showed a time-dependent accumulation of the sub-G0 population of DL cells, thus, confirming the involvement of apoptosis in tumor cells in cantharidin-mediated antitumor activity. These finding signify that the apoptosis induced by cantharidin in DL cells should involve mitochondrial-dependent pathways. It is suggested that these cantharidin-mediated changes in mitochondria may play a crucial role in its antitumor activity.

The natural compound cantharidin induces cancer cell death through inhibition of heat shock protein 70 (HSP70) and Bcl-2-associated athanogene domain 3 (BAG3) expression by blocking heat shock factor 1 (HSF1) binding to promoters.

Heat shock factor 1 (HSF1) enhances the survival of cancer cells under various stresses. The knock-out of HSF1 impairs cancer formation and progression, suggesting that HSF1 is a promising therapeutic target. To identify inhibitors of HSF1 activity, we performed cell-based screening with a library of marketed and experimental drugs and identified cantharidin as an HSF1 inhibitor. Cantharidin is a potent antitumor agent from traditional Chinese medicine. Cantharidin inhibited heat shock-induced luciferase activity with an IC50 of 4.2 µm. In contrast, cantharidin did not inhibit NF-κB luciferase reporter activity, demonstrating that cantharidin is not a general transcription inhibitor. When the HCT-116 colorectal cancer cells were exposed to heat shock in the presence of cantharidin, the induction of HSF1 downstream target proteins, such as HSP70 and BAG3 (Bcl-2-associated athanogene domain 3), was suppressed. HSP70 and its co-chaperone BAG3 have been reported to protect cells from apoptosis by stabilizing anti-apoptotic Bcl-2 family proteins. As expected, treating HCT-116 cancer cells with cantharidin significantly decreased the amounts of BCL-2, BCL-xL, and MCL-1 protein and induced apoptotic cell death. Chromatin immunoprecipitation analysis showed that cantharidin inhibited the binding of HSF1 to the HSP70 promoter and subsequently blocked HSF1-dependent p-TEFb recruitment. Therefore, the p-TEFb-dependent phosphorylation of the C-terminal domain of RNA polymerase II was blocked, arresting transcription at the elongation step. Protein phosphatase 2A inhibition with PP2CA siRNA or okadaic acid did not block HSF1 activity, suggesting that cantharidin inhibits HSF1 in a protein phosphatase 2A-independent manner. We show for the first time that cantharidin inhibits HSF1 transcriptional activity.

Antitumor effect of blister beetles: an ethno-medicinal practice in Karbi community and its experimental evaluation against a murine malignant tumor model.

ETHNOPHARMACOLOGICAL IMPORTANCE: The blister beetles Epicauta hirticornis and Mylabris cichorii are used as a folk medicine by the Karbi tribe in Karbi Anglong district of Assam, India for the treatment of different human ailments, including cancer cases. AIM OF THE STUDY: It includes field survey related to zoo-therapeutic aspects of two blister beetles in Karbi community, isolation of bio-active compound and evaluation of its antitumor potential with possible mode of action against murine Ehrlich ascites carcinoma (EAC). MATERIALS AND METHODS: The main bio-active compound of blister beetles was isolated from ethyl acetate extract and the structure was confirmed as cantharidin using NMR, IR, Mass and X-ray diffractometer. The effect of cantharidin on apoptosis, necrosis, autophagy and the apoptosis related signaling pathways were determined using different bioassays, including cell cycle analysis, mitochondrial membrane potential, western blot analysis of cytochrome c, caspases 9, 3/7 assays, and lactate dehydrogenase (LDH) assay. RESULTS: Cantharidin induced apoptosis, necrosis and autophagy cell death in EAC cells. The decrease in mitochondrial membrane potential was observed, which may help to release cytochrome c from mitochondria to cytosol. Cantharidin treatment caused up-regulation of caspases 9 and -3/7 and a decrease in LDH activity in EAC cells. CONCLUSION: The major bioactive compound of these blister beetles is cantharidin which induces severe apoptosis in EAC cells involving mitochondrial intrinsic pathway. Cantharidin-mediated inhibition of LDH activity may lead to short supply of NAD(+) and cut off energy and anabolic supply to cancer cells.

Norcantharidin inhibits pre-replicative complexes assembly of HepG2 cells.

Norcantharidin (NCTD) is currently used for anticancer therapy but the exact mechanism of action remains unknown. Pre-replicative complexes (pre-RCs) are essential for cell DNA replication and highly related to malignant proliferation. Here, we examined the inhibitory effect of NCTD on pre-RC components in HepG2 cells. We showed that NCTD induced degradation of Cdc6 and Mcm2 in a dose-dependent manner. Under 100 µM NCTD concentration, about 70% of Cdc6 and 50% of Mcm2 were degraded. In addition, the nuclear translocation of Mcm6 was inhibited by NCTD. Further studies aiming at G1 synchronous cells showed that, NCTD reduced the chromatin-bound Cdc6, Mcm2 and Mcm6. Moreover, the cells were blocked from entering the S phase and accumulated at the G1 phase when released synchronously into the cell cycle. Consistently, the DNA replication was inhibited by NCTD. Finally, the combination NCTD with Cdc6 depletion lead to more severe cytotoxicity (88%) than NCTD (52%) and Cdc6 depletion (39%) alone. A synergic cytotoxicity was observed between Cdc6 depletion and NCTD. In conclusion, our results demonstrate that NCTD inhibits pre-RC assembly; subsequently blocks the G1 to S transition; and inhibits DNA replication in HepG2 cells. Pre-RCs are an intriguing target for cancer therapy, which merits further investigations for anticancer development.

Cantharidin as an antitumor agent: a retrospective review.

This review summarizes the progress that has been made recently in the medicinal chemistry of cantharidin, a potent antitumor agent from traditional Chinese medicine. Thousands of analogs have been synthesized on the basis of cantharidin, a part of which shows excellent properties, in particular, norcantharidin and norcantharimide. Despite the enormous efforts made, the intriguing bioactivities, mechanism, indications, and their interplay are still ill-defined. This review provides our up-to-date understanding in connection with the therapeutic use, mechanism, structure-activity relationship (SAR) and interesting properties of cantharidin analogs. Considerable development in the design of cantharidin analogs, in combination with mechanistic studies, has laid a foundation for transforming novel antitumor drugs into the clinic.

Insect natural products and processes: new treatments for human disease.

In this overview, some of the more significant recent developments in bioengineering natural products from insects with use or potential use in modern medicine are described, as well as in utilisation of insects as models for studying essential mammalian processes such as immune responses to pathogens. To date, insects have been relatively neglected as sources of modern drugs although they have provided valuable natural products, including honey and silk, for at least 4-7000 years, and have featured in folklore medicine for thousands of years. Particular examples of Insect Folk Medicines will briefly be described which have subsequently led through the application of molecular and bioengineering techniques to the development of bioactive compounds with great potential as pharmaceuticals in modern medicine. Insect products reviewed have been derived from honey, venom, silk, cantharidin, whole insect extracts, maggots, and blood-sucking arthropods. Drug activities detected include powerful antimicrobials against antibiotic-resistant bacteria and HIV, as well as anti-cancer, anti-angiogenesis and anti-coagulant factors and wound healing agents. Finally, the many problems in developing these insect products as human therapeutic drugs are considered and the possible solutions emerging to these problems are described.

New alternative in treatment of callus.

The pathological transformation of the skin into a thick and hard callus due to repetitive trauma or friction is commonly known as corn. Although a variety of medical and operative treatment choices have been proposed, an ideal treatment method is yet to be defined. Effectiveness of tangential excision together with topical cantharidin has been evaluated. We used Canthacur-PS as an adjunct to excision in an outpatient setting. Canthacur-PS is a commercially available topical solution that includes 1% cantharidin, 30% salicylic acid and 5% podophyllin. The treatment has been applied to 72 patients. We found that 65 patients (90.3%) had corn on their feet and seven patients (9.7%) on their hands. Thick, hard and hyperkeratotic skin area was scraped with the help of a no. 15 blade. The solution was applied on and around the periphery (up to 1­2 mm) of the lesion with a cotton swab, and kept closed for 5 days with an antibiotic dressing. All the patients had been followed up for at least 1 year and evaluated by clinical examination and patient satisfaction query. One session of treatment succeeded in 57 (79.2%) corn patients. Two sessions in nine corn patients (12.5%), three sessions in five corn patients (6.9%) and four sessions in one patient (1.4%) were needed. Only one recurrence (1.4%) was seen. No scar formation or other side-effects were seen. Our findings show that this treatment method is a simple, minimally invasive and reliable treatment for calluses.

Spanish flies in the veterinary pharmacy in Skara--their medicinal use yesterday and to day.

In the Veterinary Museum in Skara there is also an Animal Pharmacy. One bottle originating from the 18th century is labelled Tinct. Canthar. and thus contained an extract of Spanish flies. The active substance in such a tincture is cantharidin. The use and effects of this remedy in veterinary as well as human medicine are described. The use of cantharidin in the 18th century was linked to the predominant believe that illness was caused by imbalance of the four humours of the body. Its blistering effect was thought to "draw" superfluous liquid from the body. Its pronounced toxicity made its use to disappear, but it could still be found to be used in veterinary medicine as a blister and by undiscerning people as an aphrodisiac. Recent studies has shown cantharidin to possess antitumour effect--something that Dioscorides noted in his texts from around A.D. 40-80!

Cantharidin induces apoptosis of human multiple myeloma cells via inhibition of the JAK/STAT pathway.

Multiple myeloma is an incurable B-cell malignancy requiring new therapeutic strategies in clinical settings. Interleukin (IL)-6 signaling pathways play a critical role in the pathogenesis of multiple myeloma. The traditional Chinese medicine cantharidin (CTD) has been shown to inhibit cellular proliferation and induce apoptosis of various cancer cells. The aim of this study was to investigate the possibility of CTD as a novel therapeutic agent for the patients with multiple myeloma. We investigated the in vitro effects of CTD for its antimyeloma activity, and further examined the molecular mechanisms of CTD-induced apoptosis. CTD inhibited the cellular growth of human myeloma cell lines as well as freshly isolated myeloma cells in patients. Cultivation with CTD induced apoptosis of myeloma cells in a cell-cycle-independent manner. Treatment with CTD induced caspase-3, -8, and -9 activities, and it was completely blocked by each caspase inhibitor. We further examined the effect of CTD on the IL-6 signaling pathway in myeloma cells, and found that CTD inhibited phosphorylation of STAT3 at tyrosine 705 residue as early as 1 h after treatment and down-regulated the expression of the antiapoptotic bcl-xL protein. STAT3 directly bound and activated the transcription of bcl-xL gene promoter, resulting in the induction of the expression of bcl-xL in myeloma cells. The essential role of STAT3 in CTD effects was confirmed by transfection with the constitutively active and dominant negative form of STAT3 in U266 cells. In conclusion, we have demonstrated that CTD is a promising candidate to be a new therapeutic agent in signal transduction therapy.

Effect of cantharidin, cephalotaxine and homoharringtonine on "in vitro" models of hepatitis B virus (HBV) and bovine viral diarrhoea virus (BVDV) replication.

The effect as antiviral agents versus viral hepatitis B and C of three compounds purified from natural products commonly used as remedies in traditional Chinese medicine, cantharidin, cephalotaxine and homoharingtonine, was investigated. To assess the activity of these compounds against flavivirus, we used bovine viral diarrhoea virus (BVDV) as a surrogate for hepatitis C virus (HCV). Anti-BVDV activity was determined by reduction in BVDV-RNA production and protection of infected embryonic bovine trachea (EBTr) cells against the cytopathic effect of BVDV. The effect versus hepatitis B virus (HBV) was investigated by measuring HBsAg and HBV-DNA release from hepatoblastoma HepG2 2.2.15 cells infected with HBV. As positive control we used the standard anti-HBV and anti-HCV drugs, lamivudine and ribavirin, respectively. Up to 100 microM lamivudine and ribavirin did not induce cell toxicity, whereas they induced dose-dependent anti-HBV and anti-BVDV effects, respectively. In the same range, cantharidin, cephalotaxine and homoharringtonine induced toxicity in EBTr cells and had no protective effect against BVDV. In contrast, they were able to inhibit HBV production at concentrations 10- to 100-fold lower than those inducing cell toxicity, which suggests that they are useless for the treatment of infection by flaviviruses, but potentially useful in combined therapy against hepatitis B.

Pediatric molluscum contagiosum: optimal treatment strategies.

Pediatric molluscum contagiosum virus (MCV) is a common pox viridae infection that represents a common public health issue. The spread of the virus among children is rapid and easy. The virus produces a number of substances that block immune response formation in the infected host. Despite the benign and self-limited nature of the condition, one-third of children have symptoms from, or secondary reactions to the infection, including pruritus, erythema and, occasionally, inflammation and pain. Patients with pruritus autoinoculate the virus through scratching, thereby exacerbating their conditions. While adults cope well with unanesthetized curettage of lesions, children require less painful therapeutic options. The options for therapy are manifold. Therapy should begin with gentle skin care and antipruritics to prevent symptoms, and to prevent the spread of the disease. Therapies with good efficacy and low risk of pain for the patient include in-office usage of cantharidin and the use of local anesthetics, such as topical lidocaine (lignocaine) preparations in combination with the curettage of visible lesions. Alternatively, cryosurgery can be performed to eradicate lesions in-office. At-home therapeutics are often preferred by parents and children, and include imiquimod, retinoids, and alpha-hydroxy acids. Although a variety of such at-home therapies are available, none are as effective or as rapid acting as in-office therapy. Further research in large clinical trials is required to increase knowledge on prevention, optimal treatment, and long-term outcome with this disease.