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4.1 Chromenopyrazolediones for Triple Negative Breast Paula Morales, Pilar Goya, Nadine Jagerovic
Cancer (TNBC)
are overexpressed in human breast cancer biopsies
According to the World Health Organization, breast (42,75,76). Further insights into the endocannabinoid
cancer is among the most common malignant diseases and upregulation have demonstrated a correlation between
the second leading cause of cancer death among Western CB2R expression and tumor aggressiveness in triple-
women (69). Despite recent advances in earlier detection negative breast cancer cells (42). The putative novel
and adjuvant systemic therapies, mortality rates remain cannabinoid receptor GPR55 is also highly expressed in
very high due to the emergence of refractory tumors these carcinomas (77). Consequently, the ECS represents a
associated with multidrug resistance. promising target for the treatment of TNBC (78,79).
From an immunopathological perspective, there are In this context, the antiproliferative potential of the
three main breast cancer subtypes: hormone receptor- recently reported cannabinoid-quinones derived from the
positive, HER2-positive (human epidermal growth factor chromenopyrazole scaffold was explored in models of this
receptor 2) and triple-negative tumors. Triple-negative highly aggressive breast cancer.
breast cancers (TNBC) are defined by the absence of
immunohistochemical expression of estrogen, Cell viability, using a human derived triple-negative
progesterone, and HER2 receptors. Although this breast cancer cell line, MDA-MB-231, was evaluated after
molecular subtype of breast cancer accounts for a low treatment with increasing doses of the novel para and
percentage of all breast tumors, it represents a vast number ortho-chromenopyrazolediones. All the tested
of deaths (70). TNBC show aggressive clinical behavior, cannabinoid-quinones displayed growth inhibitory effects
this fact, along with the lack of available targeted on triple-negative MDA-MB-231 breast cancer cells,
therapies, leave these patients with a bad prognosis (70– displaying low micromolar IC50 values. The para and
73). Chemotherapy with its well-known side effects is ortho-chromenopyrazolediones bearing an ethyl R
currently used as systemic treatment for this cancer (74). substituent in the pyrazole (figure 8) are the most potent
For that reason, the discovery of new targets and drugs for inhibitors of cell proliferation with IC50 values of 2.5 and
the treatment of this disease is an urgent and essential 2.8 µM respectively. Because of its antiproliferative
clinical challenge. capacity and its CB2R selective profile, compound 10
(figure 9) was selected for additional mechanistic and in
Recent evidence suggests that cannabinoid receptors vivo investigations (64).
Figure 9. Cannabinoid receptor affinity and half-maximum inhibitory concentrations (IC50) in MDA-MB-231 of ortho-
chromenopyrazoledione 10.
Compound 10 was further tested in normal Human procaspase-3 cleavage into caspase-3 confirming the
Mammary Epithelial Cells (HMEC). Interestingly, at doses proapoptotic effect of cannabinoid quinone 10 on this
triple-negative breast cancer cell line (62,64).
up to 30 µM, this cannabinoid-quinone did not exhibit
cytotoxicity in HMEC. This selective toxicity towards Chromenopyrazoledione 10 was then evaluated in a
cancer cells versus non-transformed mammary cells is murine model of TNBC. Tumor xenografts were generated
essential for the development of safer chemotherapies for in nude mice by subcutaneous inoculation of MDA-MB-
TNBC. 231 human breast adenocarcinoma cells. After four weeks
of intraperitoneal treatment with 2 mg/kg, compound 10
Deeper studies into the antitumor mechanism of action showed to effectively reduce the growth of triple-negative
of this compound were accomplished in MDA-MB-231 xenografts in this animal model. Histopathological
cells (64). According to these experiments, CB2R analysis of treated mice revealed that compound 10 did not
activation and the generation of reactive oxygen species generate signs of toxicity in organs such as liver, spleen,
(ROS) are tightly involved in the antiproliferative action of lung, heart, or colon. Volume and weight of final tumors
compound 10. Conversely, as expected, neither CB1R nor was significantly lower in all cases (64).
GPR55 mechanisms seem to be involved in the cytotoxic
effects of chromenopyrazoledione 10 (64). Summarizing, through this approach, the
chromenopyrazole scaffold has been optimized following a
Further evaluation of the cellular mechanism dual target anticancer strategy focused on triple-negative
underlying the antiproliferative effect of compound 10 led breast cancer. Cannabinoid quinone 10 was discovered as
to examine the involvement of caspase-3 in MDA-MB-231 a selective CB2R agonist with potent antiproliferative
cells. Western immunoblotting studies showed the
172 @Real Academia Nacional de Farmacia. Spain
