Potential therapeutic strategies for non - muscle invasive bladder cancer based on association of intravesical immunotherapy with P-MAPA and systemic administration of cisplatin and doxorubicin

Abstract

The present study describes the histopathological and molecular effects of P-MAPA (Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride) intravesical immunotherapy combined with systemic doxorubicin or cisplatin for treatment of non-muscle invasive bladder cancer (NMIBC) in an appropriate animal model. Our results showed an undifferentiated tumor, characterizing a tumor invading mucosa or submucosa of the bladder wall (pT1) and papillary carcinoma in situ (pTa) in the Cancer group. The histopathological changes were similar between the combined treatment with intravesical P-MAPA plus systemic Cisplatin and P-MAPA immunotherapy alone, showing decrease of urothelial neoplastic lesions progression and histopathological recovery in 80% of the animals. The animals treated systemically with cisplatin or doxorubicin singly, showed 100% of malignant lesions in the urinary bladder. Furthemore, the combined treatment with P-MAPA and Doxorubicin showed no decrease of urothelial neoplastic lesions progression and histopathological recovery. Furthermore, Akt, PI3K, NF-kB and VEGF protein levels were significantly lower in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments than other groups. In contrast, PTEN protein levels were significantly higher in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments. Thus, it could be concluded that combination of intravesical P-MAPA immunotherapy and systemic cisplatin in the NMIBC animal model was effective, well tolerated and showed no apparent signs of antagonism between the drugs. In addition, intravesical P-MAPA immunotherapy may be considered as a valuable option for treatment of BCG unresponsive patients that unmet the criteria for early cystectomy.

P-MAPA immunotherapy potentiates the effect of cisplatin on serous ovarian carcinoma through targeting TLR4 signaling

“…Furthermore, activation of IFN signaling pathway induced by P-MAPA upregulated the inducible nitric oxide synthase (iNOS) and wild-type p53 protein, resulting in apoptosis and histopathological recovery of the bladder cancer [ 15 ]. Another important therapeutic approach for bladder cancer was demonstrated by Dias et al [ 38 ], based on association of P-MAPA with systemic administration of CIS, being much more effective, well tolerated, and with no apparent signs of drug antagonism. Whether P-MAPA regulates the cellular metabolism is of interest since this model of serous OC shows significant changes in diverse metabolic pathways [ 39 , 40 ].…”

Nanopharmaceuticals and Their Applications in Bladder Cancer Therapy: a Mini Review

“…Regarding the use of doxorubicin for the treatment of NMIBC, previous studies with a commercial formulation (Doxil®), using a dose of 3.0 mg kg -1 equivalent administered intraperitoneally, demonstrated that 20% of the animals had benign lesions and 80% malignant lesions of the papillary carcinoma type in situ. 16 The results with the use of NLC-DOX developed in our laboratory showed that 20% of the animals presented benign lesions (papillary hyperplasia) and 80% malignant lesions (Table 3). On the other hand, considering the malignant lesions, 40% of them were papillary high grade (pTa), 20% papillary low grade (pTa) and 20% urothelial carcinoma invading lamina propria (pT1).…”

“…16 A drug against Cisplatin tumors refractory to BCG immunotherapy, the Valrubicin, a semisynthetic analogue of DOX showed effectiveness in less than 10% of treated patients in two years and ineffectiveness in T1 stage cases. 17 As for animals treated with GO-COOH-DOX, 20% of the animals presented normal bladder, 20% pTis-like lesions and 60% high-grade pTa.…”

Biogenic Synthesis of Important Environmental Minerals: Magnesium Phosphate Compounds and Perspectives

“…65,83 A few years ago, P-MAPA appeared as a potential candidate for intravesical therapy for non-muscle invasive bladder cancer (NMIBC). This immunomodulator was found to be important in the treatment of these types of urinary bladder cancer, 76,82,84,86,87 as well as in the prostate cancer 88 and of pancreatic cancer. 89 The most recent results with respect to NMIBC demonstrated that the immune system by BCG activation (MyD88-dependent pathway) leads to an increased inflammatory cytokines production.…”