Resistance mechanisms also involved alterations in β-Cell Lymphoma (Bcl) Bcl-2 and Bcl-xL and anti-apoptotic gene expression. To evaluate the validity of the dual approach, targeting both apoptosis and autophagy, HCQ (50 mg/kg i.p.) and an apoptosis inhibitor, ABT-737, were administered to prostatic cancer xenograft mice for 15 days. Tumor growth was significantly suppressed by a combination of drugs, with respect to HCQ or ABT-737 alone [152]. In the same way, Fenollar, et al. [153] demonstrated the efficacy of Obatoclax, a pan-Bcl-2 inhibitor, used in association with HCQ (3–60 mg/kg) or conventional in neuroblastoma-bearing mice. Positive outcomes regarded the diminution of tumor size and the complete absence of metastases in cotreated mice with respect to Obatoclax alone or with respect to control [154]. Apoptosis is also at the base of the anticancer activity of interferon-alpha, but the cancer treatment with this drug alone often leads to chemoresistance. It has been demonstrated that autophagy is in the main responsible for chemoresistance, thus the combination of interferon-alpha with inhibitors of autophagic flux may be a useful therapeutic approach. In 30 xenograft mice with head and neck squamous carcinoma, the combination of interferon-alpha with HCQ (60 mg/kg/day i.g.) and wortmannin synergistically promoted apoptosis and inhibited tumor growth [155]. In a similar fashion, Le Goff, et al. [156] investigated the potential synergic role of HCQ (30 mg/kg) in enhancing the anticancer activity of melatonin on tongue squamous cell carcinoma mouse models. The anticancer activity of melatonin depends on its pro-apoptotic effects. Nevertheless, this activity is accompanied by a pro-autophagic activity that caused chemoresistance. The coadministration of the autophagy inhibitor HCQ strongly enhanced melatonin anticancer efficacy, resulting in a smaller tumor size and weight. The effect of inhibition of autophagy on tumor growth may be enhanced if the inhibition of autophagic flux occurs when the process of autophagy is quite completed. This hypothesis has been evaluated by Brönnimann, et al. [157], administering by intravenously TAT–Beclin 1 peptide and HCQ (65 mg/kg) in murine models of breast cancer. Initially, the first agent induced the autophagic flux with the production of autophagosomes, while in the final phase of the process, the second stopped the autophagy by deacidification of lysosomes, causing the accumulation of autophagic vesicles and tumor death. HCQ was administered as HCQ-loaded liposomes, to modulate the onset of autophagy inhibition [158]. This formulation allows us to overcome the limits of HCQ usage, related to the high doses required, which is often unachievable in humans. Relatively high doses of HCQ were loaded in nanoparticles, together with the cytotoxic drug chlorambucil, demonstrating it to be safe and efficient in killing leukemia/lymphoma cancer cells in a human-mouse model of Burkitt’s lymphoma. Eight injections of nanoparticles containing 400 mg of HCQ and chlorambucil led to the overall survival of mice. These concentrations of free drugs are inapplicable, due to their high toxicity [159]. As demonstrated by Naso, Wong, Wong, Chen and Hoang [72], HCQ liposomes (60 mg/kg), together with a pH-sensitive targeting peptide that delivered HCQ into the tumor cells and lysosomes, enhanced the chemotherapic effect of conventional anticancer drug doxorubicin in animal models of melanoma. Likewise, Vayssade, et al. [160] conceived a nanogel (CA4-FeAlg/HCQ) for co-addressing vascular blocker CA4 and anti-autophagic agent HCQ (30 mg/kg) in tumor blood vessels, to synergistically treat A549 lung cancer in mice. Firstly, the release of CA4 exerted anti-angiogenic effects in the vascular site, then FeAlg/HCQ were released into small nanogels and entered in the tumor, where HCQ inhibited autophagy and iron generated ROS with a synergic antitumor effect [161]. Similarly, De Jong, et al. [162] evaluated the response of an animal model of pancreatic cancer to HCQ (5 mg/kg) and paclitaxel administration, loaded in liposomes, modified with an acid environmental sensitive peptide that is responsible for site-specific delivery. Tumor weight, together with the number of liver metastases, was significantly reduced. The administration of HCQ is associated with the inhibition of autophagy and the reduction of IL-6 that is responsible for cross-talking between cancer cells and fibroblasts. All these events avoided the formation of stroma fibrosis, allowing paclitaxel to easily reach the tumor site [104]. The synergism results are essential for HCQ activity in pancreatic cancer. In monotherapy, indeed, HCQ (800–1200 mg/day) did not achieve significant autophagy. This resulted in negligible therapeutic effects in patients with already-treated metastatic pancreatic cancer, of which only 10% were without the progressive disease after two months of therapy [163].