Vitamin D enhances the efficacy of photodynamic therapy in a murine model of breast cancer

Abstract

Cutaneous metastasis occurs more frequently in breast cancer than in any other malignancy in women, causing significant morbidity. Photodynamic therapy (PDT), which combines a porphyrin-based photosensitizer and activation by light, can be employed for breast cancer (especially cutaneous metastases) but tumor control after PDT has not surpassed traditional treatments methods such as surgery, radiation, and chemotherapy up to now. Here, we report that breast cancer nodules in mice can be effectively treated by preconditioning the tumors with 1α, 25-dihydroxyvitamin D3 (calcitriol; Vit D) prior to administering 5-aminolevulinate (ALA)-based PDT. Breast carcinoma tumors (MDA-MB-231 cells implanted subcutaneously in nude mice) received systemic Vit D (1 μg/kg) for 3 days prior to receiving ALA. The addition of Vit D increased intratumoral accumulation of protoporphyrin IX (PpIX) by 3.3 ± 0.5-fold, relative to mice receiving ALA alone. Bioluminescence imaging in vivo and immunohistochemical staining confirmed that tumor-specific cell death after ALA-PDT was markedly enhanced (36.8 ± 7.4-fold increase in TUNEL-positive nuclei; radiance decreased to 14% of control) in Vit D pretreated tumors as compared to vehicle-pretreated tumors. Vit D stimulated proliferation (10.7 ± 2.8-fold) and differentiation (9.62 ± 1.7-fold) in tumor cells, underlying an augmented cellular sensitivity to ALA-PDT. The observed enhancement of tumor responses to ALA-PDT after low, nontoxic doses of Vit D supports a new combination approach that deserves consideration in the clinical setting, and offers potential for improved remission of cutaneous breast cancer metastases.

Nitric oxide-mediated resistance to photodynamic therapy in a human breast tumor xenograft model: Improved outcome with NOS2 inhibitors

“…Such mice have been widely employed as human tumor-bearing models, one highly relevant example being animals transplanted with human melanoma which exhibited iNOS/NO-dependent progression [32]. In another relevant recent example, animals with MDA-MB-231 tumor xenografts were found to respond better to ALA-PDT after administration of vitamin D, which enhanced PpIX formation [33]. …”

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

“…ALA is metabolized to the actual PS, protoporphyrin IX (PpIX), via the heme biosynthetic pathway, PpIX accumulating initially in mitochondria (15,16). Since heme synthesis is enhanced in tumor cells, they can attain much higher levels of ALAinduced PpIX than surrounding normal cells (17), which for this type of PDT, provides a further element of tumor site specificity. The potential interference of NO with PDT was discovered by showing that Photofrin ® -PDT (18,19) or ALA-PDT (20) cure rates for various mouse-borne tumors could be significantly increased by administering NOS inhibitors, particularly for tumors with relatively high basal NO outputs.…”

Short‐term chemical pretreatment cannot replace curettage in photodynamic therapy

“…Calcitriol/calcipotriol (CAL) is the hormonally active metabolite of vitamin D, and recent murine and human studies show that pretreatment with CAL significantly enhances PpIX fluorescence during MAL and ALA PDT . CAL is believed to mediate this enhancement through alterations in the expression of two enzymes in the heme synthesis; coproporphyrinogen expression is increased while ferrochelatase expression is decreased .…”